Quinolinyloxyphenylsulfonamides

ABSTRACT

The present invention relates to quinolinyloxyphenylsulfonamides and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts of these quinolinyloxyphenylsulfonamide compounds as well as pharmaceutical compositions containing at least one of these compounds together with at least one pharmaceutically acceptable carrier, excipient and/or diluent. Said quinolinyloxyphenylsulfonamides are useful for prophylaxsis, treatment and/or after-treatment of hyperproliferative disorders, such as cancer, tumors and particularly cancer metastases.

The present invention relates to quinolinyloxyphenylsulfonamides andstereoisomeric forms, solvates, hydrates and/or pharmaceuticallyacceptable salts of these quinolinyloxyphenylsulfonamide compounds aswell as pharmaceutical compositions containing at least one of thesecompounds together with at least one pharmaceutically acceptablecarrier, excipient and/or diluent. Said quinolinyloxyphenylsulfonamidesare useful for prophylaxsis, treatment and/or after-treatment ofhyperproliferative disorders, such as cancer, tumors and particularlycancer metastases.

BACKGROUND OF THE INVENTION

The international patent application PCT/EP2009/002798 refers to similarcompounds which are inhibitors of receptor tyrosine kinases of the AXLreceptor family. These compounds are suitable for the treatment orprevention of disorders associated with, accompanied by or caused byhyperfunction of a receptor of the AXL family. The compounds ofPCT/EP2009/002798 are suitable for the treatment of hyperproliferativedisorders, such as cancer and particularly cancer metastases.

It is object of the present invention to provide further compounds andpharmaceutically acceptable salts thereof which can be used aspharmaceutically active agents, especially for prophylaxis, treatmentand after-treatment of cancer, tumors and particularly cancermetastases.

The object of the present invention is solved by the teaching of theindependent claims. Further advantageous features, aspects and detailsof the invention are evident from the dependent claims, the description,and the examples of the present application.

The novel quinolinyloxyphenylsulfonamides according to the presentinvention are represented by the following general formula (I)

wherein—R¹ or —R² represents —O—X—R⁸;if —R¹ represents —O—X—R⁸ than —R² represents —H, —OH, —OCH₃, —OCF₃,—OC₂H₅, —OC₃H₇, —OCH₂CH₂—OCH₃, —OCH₂CH₂—OC₂H₅;if —R² represents —O—X—R⁸ than —R¹ represents —H, —OH, —OCH₃, —OCF₃,—OC₂H₅, OC₃H₇, —OCH₂CH₂—OCH₃, —OCH₂CH₂—OC₂H₅;—X— represents —CR¹¹R¹²—, —CR¹¹R¹²—CR¹³R¹⁴—, —CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—,—CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—,—CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—,—CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²¹R²²—, —(CH₂)_(n)—NH—, —CO—,—(CH₂)_(n)—CO—, —(CH₂)_(n)—NH—CO—NH—, —(CH₂)_(n)—NH—CO—,—(CH₂)_(n)—NH—CO—O—, —(CH₂)_(n)—CO—NH—, —(CH₂)_(n)—O—CO—NH—,—(CH₂)_(n)—O—CO—, —(CH₂)_(n)—O—, —(CH₂)_(n)—,n is an integer selected from 1, 2, 3, 4, 5 and 6;—R³, —R⁴, —R⁵, —R⁶ are independently of each other selected fromhydrogen, halogen, nitro, C₁₋₆ alkyl, C₃-C₁₀-cycloalkyl, C₁₋₆ alkoxy,wherein the C₁₋₆ alkyl, C₃-C₁₀-cycloalkyl or C₁₋₆ alkoxy groups areoptionally mono- or polysubstituted by hydroxyl, halogen, C₁₋₄ alkyland/or C₁₋₄ alkoxy, wherein the C₁₋₄ alkyl and/or C₁₋₄ alkoxy groups areoptionally mono- or polysubstituted by hydroxyl and/or halogen.—R⁷ represents(i) a saturated or unsaturated three- to twelve-membered carbocyclic orheterocyclic ring system which is optionally mono- or polysubstituted byhydroxy, C₁₋₆ alkyl, C₃-C₁₀-cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, a halogen atom, or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group, and the C₁₋₆ alkyl,C₃-C₁₀-cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy groupsare optionally substituted by a halogen atom or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group,(ii) C₁₋₆ alkyl or C₁₋₆ alkoxy which is unsubstituted or substituted bya saturated or unsaturated three- to twelve-membered carbocyclic orheterocyclic ring system which is optionally mono- or polysubstituted byhydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, a halogenatom, or a saturated or unsaturated three- to eight-membered carbocyclicor heterocyclic group, and the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ alkoxy groups are optionally substituted by a halogen atom or asaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group,(iii) a nitrogen atom substituted with a saturated or unsaturated three-to twelve-membered or heterocyclic ring system which is optionally mono-or polysubstituted by hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, a halogen atom, or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group, and the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy groups are optionallysubstituted by a halogen atom or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group,—R⁸ represents hydrogen, hydroxyl, halogen, C₁₋₆ alkoxy, C₁₋₆alkylcarbonyl, carboxyl, C₃-C₁₀-cycloalkyl, C₁₋₆ alkoxycarbonyl, aheterocyclic group, a heterocycloalkyl group with one or two heteroatomsselected from O, N, S and 2 to 6 carbon atoms, C₁₋₆-alkyl,—NH—CO—NR⁹R¹⁰, —CO—NR⁹R¹⁰, —NR⁹R¹⁰;—R⁹ and —R¹⁰ are independently of each other selected from hydrogen,C₃-C₆-cycloalkyl, C₁₋₆ alkyl optionally substituted by hydroxyl, halogenand/or C₁₋₄ alkoxy or—R⁹ and —R¹⁰ may combine with the nitrogen atom attached thereto to forma saturated or unsaturated five- or six-membered heterocyclic group,wherein the heterocyclic group is optionally substituted by hydroxyl,amino, halogen, —COOH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ acyloxy, asaturated or unsaturated three- to twelve-membered carbocyclic orheterocyclic ring system,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl and/or C₁₋₆ acyloxy groups areoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to twelve-membered carbocyclic or heterocyclic ringsystem;wherein in the amino group one or both hydrogen atoms on said aminogroup are optionally substituted by C₁₋₆ alkyl or a saturated orunsaturated three- to twelve-membered carbocyclic or heterocyclic ringsystem, and the C₁₋₆ alkyl group is optionally substituted by hydroxyl,C₁₋₆ alkoxy, or a saturated or unsaturated three- to twelve-memberedcarbocyclic or heterocyclic ring system;wherein the saturated or unsaturated three- to twelve-memberedcarbocyclic or heterocyclic ring system is optionally substituted byhydroxyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, or a saturated or unsaturated three- to twelve-memberedcarbocyclic or heterocyclic ring system, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl groups are optionally substituted by hydroxyl,C₁₋₆ alkoxy, or a saturated or unsaturated three- to twelve-memberedcarbocyclic or heterocyclic ring system; when the carbocyclic orheterocyclic group is substituted by two C₁₋₆ alkyl groups, the twoalkyl groups may combine together to form an alkylene chain; and thecarbocyclic or heterocyclic group may be condensed with anothersaturated or unsaturated five- to seven-membered carbocyclic orheterocyclic group to form a bicyclic group.

Preferably —R⁹ is selected from hydrogen, C₁₋₆-alkyl which is optionallysubstituted by hydroxyl, halogen and/or C₁₋₄-alkoxy and —R¹⁰ is selectedfrom C₁₋₆-alkyl which is optionally substituted by hydroxyl, halogenand/or C₁₋₄-alkoxy.

R¹¹-R²² represent independently of each other linear or branched,substituted or unsubstituted C₁-C₂₀-alkyl, —H, —OH, —OCH₃, —OC₂H₅,—OC₃H₇, —O-cyclo-C₃H₅, —OCH(CH₃)₂, —OC(CH₃)₃, —OC₄H₉, —OPh, —OCH₂-Ph,—OCPh₃, —SH, —SCH₃, —SC₂H₅, —SC₃H₇, —S-cyclo-C₃H₅, —SCH(CH₃)₂,—SC(CH₃)₃, —NO₂, —F, —Cl, —Br, —I, —N₃, —CN, —OCN, —NCO, —SCN, —NCS,—CHO, —COCH₃, —COC₂H₅, —COC₃H₇, —CO-cyclo-C₃H₅, —COCH(CH₃)₂, —COC(CH₃)₃,—COOH, —COCN, —COOCH₃, —COOC₂H₅, —COOC₃H₇, —COO-cyclo-C₃H₅,—COOCH(CH₃)₂, —COOC(CH₃)₃, —OOC—CH₃, —OOC—C₂H₅, —OOC—C₃H₇,—OOC-cyclo-C₃H₅, —OOC—CH(CH₃)₂, —OOC—C(CH₃)₃, —CONH₂, —CONHCH₃,—CONHC₂H₅, —CONHC₃H₇, —CONH-cyclo-C₃H₅, —CONH[CH(CH₃)₂], —CONH[C(CH₃)₃],—CON(CH₃)₂, —CON(C₂H₅)₂, —CON(C₃H₇)₂, —CON(cyclo-C₃H₅)₂,—CON[CH(CH₃)₂]₂, —CON[C(CH₃)₃]₂, —NH₂, —NHCH₃, —NHC₂H₅, —NHC₃H₇,—NH-cyclo-C₃H₅, —NHCH(CH₃)₂, —NHC(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(C₃H₇)₂,—N(cyclo-C₃H₅)₂, —N[CH(CH₃)₂]₂, —N[C(CH₃)₃]₂, —SOCH₃, —SOC₂H₅, —SOC₃H₇,—SO-cyclo-C₃H₅, —SOCH(CH₃)₂, —SOC(CH₃)₃, —SO₂CH₃, —SO₂C₂H₅, —SO₂C₃H₇,—SO₂-cyclo-C₃H₅, —SO₂CH(CH₃)₂, —SO₂C(CH₃)₃, —SO₃H, —SO₃CH₃, —OCHF₂,—SO₃C₂H₅, —SO₃C₃H₇, —SO₃-cyclo-C₃H₅, —SO₃CH(CH₃)₂, —SO₃C(CH₃)₃, —OCF₃,—OC₂F₅, —O—COOCH₃, —O—COOC₂H₅, —O—COOC₃H₇, —O—COO-cyclo-C₃H₅,—O—COOCH(CH₃)₂, —O—COOC(CH₃)₃, —NH—CO—NH₂, —NH—CO—NHCH₃, —NH—CO—NHC₂H₅,—NH—CO—NHC₃H₇, —NH—CO—NH-cyclo-C₃H₅, —NH—CO—NH[CH(CH₃)₂],—NH—CO—NH[C(CH₃)₃], —NH—CO—N(CH₃)₂, —NH—CO—N(C₂H₅)₂, —NH—CO—N(C₃H₇)₂,—NH—CO—N(cyclo-C₃H₅)₂, —NH—CO—N[CH(CH₃)₂]₂, —NH—CO—N[C(CH₃)₃]₂,—NH—CS—NH₂, —NH—CS—NH-cyclo-C₃H₅, —NH—CS—NHC₃H₇, —NH—CS—NH[CH(CH₃)₂],—NH—CS—NH[C(CH₃)₃], —NH—CS—N(CH₃)₂, —NH—CS—N(C₂H₅)₂, —NH—CS—N(C₃H₇)₂,—NH—CS—N(cyclo-C₃H₅)₂, —NH—CS—N[CH(CH₃)₂]₂, —NH—CS—N[C(CH₃)₃]₂,—NH—C(═NH)—NH₂, —NH—C(═NH)—NHCH₃, —NH—C(═NH)—NHC₂H₅, —NH—CS—NHC₂H₅,—NH—C(═NH)—NHC₃H₇, —NH—C(═NH)—NH-cyclo-C₃H₅, —NH—C(═NH)—NH[CH(CH₃)₂],—NH—C(═NH)—NH[C(CH₃)₃], —NH—CS—NHCH₃, —NH—C(═NH)—N(CH₃)₂,—NH—C(═NH)—N(C₂H₅)₂, —NH—C(═NH)—N(C₃H₇)₂, —NH—C(═NH)—N(cyclo-C₃H₅)₂,—NH—C(═NH)—N[CH(CH₃)₂]₂, —NH—C(═NH)—N[C(CH₃)₃]₂, —O—CO—NH₂, —O—CO—NHCH₃,—O—CO—NHC₂H₅, —O—CO—NHC₃H₇, —O—CO—NH-cyclo-C₃H₅, —O—CO—NH[CH(CH₃)₂],—O—CO—NH[C(CH₃)₃], —O—CO—N(CH₃)₂, —O—CO—N(C₂H₅)₂, —O—CO—N(C₃H₇)₂,—O—CO—N(cyclo-C₃H₅)₂, —O—CO—N[CH(CH₃)₂]₂, —O—CO—N[C(CH₃)₃]₂, —O—CO—OCH₃,—O—CO—OC₂H₅, —O—CO—OC₃H₇, —O—CO—O-cyclo-C₃H₅, —O—CO—OCH(CH₃)₂,—O—CO—OC(CH₃)₃, —CH₂F—CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂Br—CHBr₂,—CBr₃, —CH₂I—CHI₂, —Cl₃, —CH₂—CH₂F—CH₂—CHF₂, —CH₂—CF₃, —CH₂—CH₂Cl,—CH₂—CHCl₂, —CH₂—CCl₃, —CH₂—CH₂Br—CH₂—CHBr₂, —CH₂—CBr₃, —CH₂—CH₂I,—CH₂—CHI₂, —CH₂—Cl₃, —CH₃, —C₂H₅, —C₃H₇, -cyclo-C₃H₅, —CH(CH₃)₂,—C(CH₃)₃, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, -Ph, —CH₂-Ph,—CPh₃, —CH═CH₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C₂H₄—CH═CH₂,—CH═C(CH₃)₂, —C≡CH, —C≡C—CH₃, —CH₂—C≡CH, —Si(CH₃)₃, and stereoisomericforms, solvates, hydrates and/or pharmaceutically acceptable saltsthereof.

As used herein, the term “C₁₋₆ alkyl” or “linear or branchedC₁-C₆-alkyl” refers to —CH₃, —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —CH(CH₃)—C₃H₇,—CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C₅H₁₁, —C(CH₃)₂—C₂H₅,—CH₂—C(CH₃)₃, —CH(C₂H₅)₂, —C₂H₄—CH(CH₃)₂, —C₆H₁₃, —C₃H₆—CH(CH₃)₂,—C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,—CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,—CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃, and—CH(CH₃)—C(CH₃)₃, wherein in the afore-mentioned groups one or morehydrogen atoms can be replaced by —OH, —OCH₃, —OC₂H₅, —SH, —SCH₃,—SC₂H₅, —NO₂, —F, —Cl, —Br, —I, —N₃, —COCH₃, —COC₂H₅, —COOCH₃, —COOC₂H₅,—OOC—CH₃, —OOC—C₂H₅, —COOH, —CONH₂, —CON(CH₃)₂, —CON(C₂H₅)₂, —NH₂,—NHCH₃, —NHC₂H₅, —N(CH₃)₂, —N(C₂H₅)₂, —SOCH₃, —SOC₂H₅, —SO₃H, —OCF₃,—CF₃, —C≡CH. Preferred are —CH₃, —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, and —C₅H₁₁. Especially preferredare —CH₃, —C₂H₅, —C₃H₇.

As used herein, the term “C₃-C₁₀-cycloalkyl” or “carbocyclic group”refers to

Preferred are the following cycloalkyls:

As used herein, the term “C₂₋₆ alkenyl” or “linear or branchedC₂-C₆-alkenyl” refers to —CH═CH₂, —CH₂—CH═CH₂, —CH═CH—CH₃, —C₂H₄—CH═CH₂,—CH═CH—C₂H₆, —CH₂—C(CH₃)═CH₂, —CH(CH₃)—CH═CH, —CH═C(CH₃)₂,—C(CH₃)═CH—CH₃, —CH═CH—CH═CH₂, —C₃H₆—CH═CH₂, —C₂H₄—CH═CH—CH₃,—CH₂—CH═CH—C₂H₅, —CH═CH—C₃H₇, —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃,—CH═CH—CH₂—CH═CH₂, —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂,—CH═CH—C(CH₃)═CH₂, —C₂H₄—C(CH₃)═CH₂, —CH₂—CH(CH₃)—CH═CH₂,—CH(CH₃)—CH₂—CH═CH₂, —CH₂—CH═C(CH₃)₂, —CH₂—C(CH₃)═CH—CH₃,—CH(CH₃)—CH═CH—CH₃, —CH═CH—CH(CH₃)₂, —CH═C(CH₃)—C₂H₅, —C(CH₃)═CH—C₂H₅,—C(CH₃)═C(CH₃)₂, —C(CH₃)₂—CH═CH₂, —CH(CH₃)—C(CH₃)═CH₂,—C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —C₄H₈—CH═CH₂,—C₃H₆—CH═CH—CH₃, —C₂H₄—CH═CH—C₂H₅, —CH₂—CH═CH—C₃H₇, —CH═CH—C₄H₉,—C₃H₆—C(CH₃)═CH₂, —C₂H₄—CH(CH₃)—CH═CH₂, —CH₂—CH(CH₃)—CH₂—CH═CH₂,—CH₂—CH═CH—CH₃, —CH(CH₃)—C₂H₄—CH═CH₂, —C₂H₄—CH═C(CH₃)₂,—C₂H₄—C(CH₃)═CH—CH₃, —CH₂—CH(CH₃)—CH═CH—CH₃, —CH(CH₃)—CH₂—CH═CH—CH₃,—C(CH₃)═CH₂, —CH₂—CH═CH—CH(CH₃)₂, —CH₂—CH═C(CH₃)—C₂H₆,—CH₂—C(CH₃)═CH—C₂H₅, —CH(CH₃)—CH═CH—C₂H₅, —CH═CH—CH₂—CH(CH₃)₂,—CH═CH—CH(CH₃)—C₂H₅, —CH═C(CH₃)—C₃H₇, —C(CH₃)═CH—C₃H₇,—CH₂—CH(CH₃)—C(CH₃)═CH₂, —CH(CH₃)—CH₂—C(CH₃)═CH₂,—CH(CH₃)—CH(CH₃)—CH═CH₂, —CH₂—C(CH₃)₂—CH═CH₂, —C(CH₃)₂—CH₂—CH═CH₂,—CH₂—C(CH₃)═C(CH₃)₂, —CH(CH₃)—CH═C(CH₃)₂, —C(CH₃)₂—CH═CH—CH₃,—CH(CH₃)—C(CH₃)═CH—CH₃, —CH═C(CH₃)—CH(CH₃)₂, —C(CH₃)═CH—CH(CH₃)₂,—C(CH₃)═C(CH₃)—C₂H₅, —C(CH₃)₂—C(CH₃)═CH₂, —CH(C₂H₅)—C(CH₃)═CH₂,—C(CH₃)(C₂H₅)—CH═CH₂, —CH(CH₃)—C(C₂H₅)═CH₂, —CH₂—C(C₂H₅)═CH—CH₃,—C[CH₂—CH(CH₃)₂]═CH₂, —C₂H₄—CH═CH—CH═CH₂, —CH₂—CH═CH—CH₂—CH═CH₂,—CH═CH—C₂H₄—CH═CH₂, —CH═CH—C(CH₃)₃, —CH₂—CH═CH—CH═CH—CH₃,—CH═CH—CH₂—CH═CH—CH₃, —C[CH(CH₃)(C₂H₅)]═CH₂, —CH═CH—CH═CH—C₂H₅,—CH₂—CH═CH—C(CH₃)═CH₂, —C(C₂H₅)═CH—C₂H₅, —CH₂—CH═C(CH₃)—CH═CH₂,—CH₂—C(CH₃)═CH—CH═CH₂, —C(C₂H₅)═C(CH₃)₂, —CH(CH₃)—CH═CH—CH═CH₂,—CH═CH—CH₂—C(CH₃)═CH₂, —C(C₄H₉)═CH₂, —CH═CH—CH(CH₃)—CH═CH₂,—CH═C(CH₃)—CH₂—CH═CH₂, —C[C(CH₃)₃]═CH₂, —CH═C(CH₃)—CH═CH—CH₃,—C(CH₃)═CH—CH₂—CH═CH₂, —CH(C₂H₅)—CH═CH—CH₃, —CH═CH—C(CH₃)═CH—CH₃,—CH═CH—CH═C(CH₃)₂, —C(C₃H₇)═CH—CH₃, —C(CH₃)═CH—CH═CH—CH₃,—CH═C(CH₃)—C(CH₃)═CH₂, —CH₂—C(C₃H₇)═CH₂, —C(CH₃)═CH—C(CH₃)═CH₂,—C(CH₃)═C(CH₃)—CH═CH₂, and —CH═CH—CH═CH—CH═CH₂.

Preferred are —CH═CH₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃,—C₂H₄—CH═CH₂, —CH₂—CH═CH—CH₃. Especially preferred are—CH═CH₂—CH₂—CH═CH₂.

As used herein, the term “C₂₋₆ alkynyl” or “linear or branchedC₂-C₆-alkynyl” refers to —C≡CH, —C≡C—CH₃, —CH₂—C≡CH, —C₂H₄—C≡CH,—CH₂—C≡C—CH₃, —C≡C—C₂H₅, —C₃H₆—C≡CH, —C₂H₄—C≡C—CH₃, —CH₂—C═C—C₂H₆,—C═C—C₃H₇, —CH(CH₃)—C≡CH, —CH₂—CH(CH₃)—C≡CH, —CH(CH₃)—CH₂—C≡CH,—CH(CH₃)—C≡C—CH₃, —C₄H₈—C≡CH, —C₃H₆—C≡C—CH₃, —C₂H₄—C≡C—C₂H₅,—CH₂—C≡C—C₃H₇, —C₂H₄—CH(CH₃)—C≡CH, —CH₂—CH(CH₃)—CH₂—C≡CH,—CH(CH₃)—C₂H₄—C≡CH, —CH₂—CH(CH₃)—C≡C—CH₃, —CH(CH₃)—CH₂—C≡C—CH₃,—CH(CH₃)—C≡C—C₂H₅, —CH₂—C≡C—CH(CH₃)₂, —C≡C—CH(CH₃)—C₂H₅,—C≡C—CH₂—CH(CH₃)₂, —C≡C—C₄H₉, —C≡C—C(CH₃)₃, —CH(C₂H₅)—C≡C—CH₃,—C(CH₃)₂—C≡C—CH₃, —CH(C₂H₅)—CH₂—C≡CH, —CH₂—CH(C₂H₅)—C≡CH,—C(CH₃)₂—CH₂—C≡CH, —CH₂—C(CH₃)₂—C≡CH, —CH(CH₃)—CH(CH₃)—C≡CH,—CH(C₃H₇)—C≡CH, —C(CH₃)(C₂H₅)—C≡CH, —C≡C—C≡CH, —CH₂—C≡C—C≡CH,—C≡C—C≡C—CH₃, —CH(C≡CH)₂, —C₂H₄—C≡C—C≡CH, —CH₂—C═C—CH₂—C≡CH,—C≡C—C₂H₄—C≡CH, —CH₂—C≡C—C≡C—CH₃, —C≡C—CH₂—C≡C—CH₃, —C≡C—C≡C—C₂H₅,—C≡C—CH(CH₃)—C≡CH, —CH(CH₃)—C≡C—C≡CH, —CH(C≡CH)—CH₂—C≡CH, —C(C≡CH)₂—CH₃,—CH₂—CH(C≡CH)₂, —CH(C≡CH)—C≡C—CH₃. Preferred are —C≡CH and —C≡C—CH₃.

As used herein, the term “aryl” or “carbocyclic group” refers to phenyl,indenyl, indanyl, naphthyl, 1,2-dihydro-naphthyl, 2,3-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl(tetralinyl), fluorenyl, anthryl(anthracenyl),9,10-dihydroanthryl, 1,2,3,4-tetrahydro-anthryl,1,2,3,4,5,6,7,8-octahydro-anthryl, azulenyl, diphenyl methyl, benzyl,triphenylmethyl(trityl), styryl, naphthoquinonyl, acenaphthyl,anthraquinonyl, phenanthryl(phenanthrenyl) and especially to a mono- orbicyclic 6 to 10 membered ring system, preferably phenyl or napthyl.

As used herein, the term “heteroaryl” or “heterocyclic ring” or“heterocyclic group” refers to heteroaromatic groups which have from 5to 10 ring atoms, from 1 to 4 of which are selected from O, N and/or S.Preferred groups have 1 or 2 heteroatoms in a 5- or 6-membered aromaticring. Mono and bicyclic ring systems are included. Typical heteroarylgroups which are at least partially aromatic include pyridyl, furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, pyridazinyl, pyrimidyl, pyrazinyl,1,3,5-triazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, indolizinyl,indolyl, isoindolyl, benzo[b]furyl, thiophenyl, benzo[b]thienyl,indazolyl, benzimidazolyl, benzthiazolyl, thiazolyl, purinyl,quinolizinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl,1,8-naphthyridinyl, tetrahydroquinolyl, benzooxazolyl, chrom-2-onyl,indazolyl, indenyl. Said herteroaryl groups may further be substitutedby one, two, three, four, five or more substituents selected from thegroup consisting of R¹⁸-R³⁰, linear or branched C₁-C₆-alkyl,C₃-C₆-cycloalkyl, linear or branched C₂-C₆-alkenyl, linear or branchedC₂-C₆-alkynyl and aryl.

Preferred heterocyclic groups from which also R⁷ can be selected are:

R⁷ can also be selected from the above-mentioned heterocyclic groups. Inaddition R⁷ can also stand for the following residue:

wherein R²³ to R²⁷ are independently of each other selected from thesubstituents mentioned below.

Preferred heterocyclic —NR⁹R¹⁰ groups are:

Said preferred herteroaryl groups and heterocyclic groups may further besubstituted by one, two, three, four, five or more substituents selectedfrom the group consisting of R²³—R³⁵, linear or branched C₁-C₆-alkyl,C₃-C₁₀-cycloalkyl, linear or branched C₂-C₆-alkenyl, linear or branchedC₂-C₆-alkynyl and aryl.

As used herein, the term “heterocyclic group” or “heterocyclic ring” or“heterocyclic ring system” or “heterocyclyl” refers to carbocycleshaving at least one heteroatom in the ring such as oxygen, nitrogen, orsulfur. Such heterocycles may be saturated or partially unsaturated butnot aromatic. Examples for heterocyclic residues are 1,3-dioxolane,benzo[1,3]dioxolyl, pyrazolinyl, pyranyl, thiomorpholinyl,pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl,pyrrolinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl,oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl,thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl,pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl.

Aryl refers to phenyl, substituted phenyl and heteroaryl, whereinsubstituted phenyl and heteroaryl have the meanings as defined above.

As used herein, the term “C₁-C₆ alkyloxy” or “C₁-C₆ alkoxy” refers tothe residue —O—C₁-C₆-alkyl, wherein C₁-C₆-alkyl has the meanings asdefined above. The following C₁-C₆ alkoxy groups are preferred —O—CH₃,—O—C₂H₅, —O—C₃H₇, —O—CH(CH₃)₂, —O—C₄H₉, —O—CH₂—CH₂—CH(CH₃)₂,—O—CH(CH₃)—C₂H₅, —O—C(CH₃)₃, and —O—C₅H₁₁. Most preferred are —O—CH₃,—O—C₂H₅ and —O—C₃H.

As used herein, the term “C₁-C₆ alkyloxycarbonyl” or “C₁-C₆alkoxycarbonyl” refers to the residue —CO—O—C₁-C₆-alkyl, whereinC₁-C₆-alkyl has the meanings as defined above. Preferred C₁-C₆alkoxycarbonyl groups are —CO—OCH₃, —CO—OC₂H₅, —CO—OC₃H₇, —CO—OCH(CH₃)₂,—CO—OC₄H₉, —CO—OCH₂—CH(CH₃)₂, —CO—OCH(CH₃)—C₂H₅, —CO—OC(CH₃)₃, and—CO—OC₅H₁₁. Most preferred are —CO—OCH₃, —CO—OC₂H₅, —CO—OC₃H₇.

As used herein, the term “C₁-C₆ alkylcarbonyl” or “C₁-C₆ alkanoyl” or“C₁-C₆ acyl” refers to the residue —CO—C₁-C₆-alkyl, wherein C₁-C₆-alkylhas the meanings as defined above. Preferred C₁-C₆ acyl groups are—CO—CH₃, —CO—C₂H₅, —CO—C₃H₇, —CO—CH(CH₃)₂, —CO—C₄H₉, —CO—CH₂—CH(CH₃)₂,—CO—CH(CH₃)—C₂H₅, —CO—C(CH₃)₃, and —CO—C₅H₁₁. Most preferred are—CO—CH₃, —CO—C₂H₅, —CO—C₃H₇.

As used herein, the term “C₁-C₆ alkylcarbonyloxy” or “C₁-C₆ alkanoyloxy”or “C₁-C₆ acyloxy” refers to the residue —O—CO—C₁-C₆-alkyl, whereinC₁-C₆-alkyl has the meanings as defined above. Preferred C₁-C₆ acyloxygroups are —O—CO—CH₃, —O—CO—C₂H₅, —O—CO—C₃H₇, —O—CO—CH(CH₃)₂,—O—CO—C₄H₉, —O—CO—CH₂—CH(CH₃)₂, —O—CO—CH(CH₃)—C₂H₅, —O—CO—C(CH₃)₃, and—O—CO—C₅H₁₁. Most preferred are —O—CO—CH₃, —O—CO—C₂H₅, —O—CO—C₃H₇.

The term “substituted” or “substituted alkyl”, “substituted cycloalkyl”,“substituted heterocyclyl”, “substituted aryl”, “substitutedheteroaryl”, “substituted heterocyclic group”, “substitutedcarbobicyclic group” respectively shall refer to the addressed residuesuch as “alkyl”, “cycloalkyl”, “heterocyclyl”, “aryl”, or “heteroaryl”bearing one, two, three, four, five or more, preferably one or twosubstituents R²³ to R³⁵ independently selected from the following group:

—OH, —OCH₃, —OC₂H₅, —OC₃H₇, —O-cyclo-C₃H₅, —OCH(CH₃)₂, —OC(CH₃)₃,—OC₄H₉, —OPh, —OCH₂-Ph, —OCPh₃, —SH, —SCH₃, —SC₂H₅, —SC₃H₇,—S-cyclo-C₃H₅, —SCH(CH₃)₂, —SC(CH₃)₃, —NO₂, —F, —Cl, —Br, —I, —N₃, —CN,—OCN, —NCO, —SCN, —NCS, —CHO, —COCH₃, —COC₂H₅, —COC₃H₇, —CO-cyclo-C₃H₅,—COCH(CH₃)₂, —COC(CH₃)₃, —COOH, —COCN, —COOCH₃, —COOC₂H₅, —COOC₃H₇,—COO-cyclo-C₃H₅, —COOCH(CH₃)₂, —COOC(CH₃)₃, —OOC—CH₃, —OOC—C₂H₅,—OOC—C₃H₇, —OOC-cyclo-C₃H₅, —OOC—CH(CH₃)₂, —OOC—C(CH₃)₃, —OCHF₂, —CONH₂,—CONHCH₃, —CONHC₂H₅, —CONHC₃H₇, —CONH-cyclo-C₃H₅, —CONH[CH(CH₃)₂],—CONH[C(CH₃)₃], —CON(CH₃)₂, —CON(C₂H₅)₂, —CON(C₃H₇)₂, —CON(cyclo-C₃H₅)₂,—CON[CH(CH₃)₂]₂, —CON[C(CH₃)₃]₂, —NH₂, —NHCH₃, —NHC₂H₅, —NHC₃H₇,—NH-cyclo-C₃H₅, —NHCH(CH₃)₂, —NHC(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(C₃H₇)₂,—N(cyclo-C₃H₅)₂, —N[CH(CH₃)₂]₂, —N[C(CH₃)₃]₂, —SOCH₃, —SOC₂H₅, —SOC₃H₇,—SO-cyclo-C₃H₅, —SOCH(CH₃)₂, —SOC(CH₃)₃, —SO₂CH₃, —SO₂C₂H₅, —SO₂C₃H₇,—SO₂-cyclo-C₃H₅, —SO₂CH(CH₃)₂, —SO₂C(CH₃)₃, —SO₃H, —SO₃CH₃, —SO₃C₂H₅,—SO₃C₃H₇, —SO₃-Cyclo-C₃H₅, —SO₃CH(CH₃)₂, —SO₃C(CH₃)₃, —OCF₃, —OC₂F₅,—O—COOCH₃, —O—COOC₂H₅, —O—COOC₃H₇, —O—COO-cyclo-C₃H₅, —O—COOCH(CH₃)₂,—O—COOC(CH₃)₃, —NH—CO—NH₂, —NH—CO—NHCH₃, —Si(CH₃)₃, —NH—CO—NHC₂H₅,—NH—CO—NHC₃H₇, —NH—CO—NH-cyclo-C₃H₅, —O—CO—NH₂, —O—CO—NHCH₃,—O—CO—NHC₂H₅, —O—CO—NHC₃H₇, —O—CO—NH-cyclo-C₃H₅, —O—CO—NH[CH(CH₃)₂],—O—CO—NH[C(CH₃)₃], —O—CO—N(CH₃)₂, —O—CO—N(C₂H₅)₂, —O—CO—N(C₃H₇)₂,—O—CO—N(cyclo-C₃H₅)₂, —O—CO—N[CH(CH₃)₂]₂, —O—CO—N[C(CH₃)₃]₂, —O—CO—OCH₃,—O—CO—OC₂H₅, —O—CO—OC₃H₇, —O—CO—O-cyclo-C₃H₅, —O—CO—OCH(CH₃)₂,—O—CO—OC(CH₃)₃, —CH₂F—CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂Br—CHBr₂,—CBr₃, —CH₂₁—CHI₂, —Cl₃, —CH₂—CH₂F—CH₂—CHF₂, —CH₂—CF₃, —CH₂—CH₂Cl,—CH₂—CHCl₂, —CH₂—CCl₃, —CH₂—CH₂Br—CH₂—CHBr₂, —CH₂—CBr₃, —CH₂—CH₂I,—CH₂—CHI₂, —CH₂—Cl₃, -cyclo-C₃H₅, -Ph, —CH₂-Ph, —CPh₃, —CH═CH₂,—CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C₂H₄—CH═CH₂, —CH═C(CH₃)₂, —C≡CH,—C≡C—CH₃, —CH₂—C≡CH, —CH₃, —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —CH(CH₃)—C₃H₇,—CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —₅H₁₁, —C(CH₃)₂—C₂H₅,—CH₂—C(CH₃)₃, —CH(C₂H₅)₂, —C₂H₄—CH(CH₃)₂, —C₆H₁₃, —C₃H₆—CH(CH₃)₂,—C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,—CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,—CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃, and—CH(CH₃)—C(CH₃)₃.

Preferred residues R⁸—X—O— are selected from:

whereinthe substituent —R¹³ has the meanings as defined herein;the substituent —R²² refers to the residues disclosed above andpreferably to phenyl, benzyl, C₁-C₆-alkyl, pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, —OH, —CH₂—OH, —C₂H₄—OH, —OCH₃, —CH₂—OCH₃or —C₂H₄—OCH₃.

Further preferred compounds of the present invention are such compoundswherein R⁸—X—O— is selected from:

whereinthe substituents —R⁹, —R¹⁰, —R¹³ and C₁-C₆-alkyl have the meanings asdefined herein.

Another group of preferred compounds has residues R⁸—X—O— selected fromthe following groups:

whereinthe substituent —R¹³ has the meanings as defined above.

Preferred are also compounds of the general formula (I)

whereinone of —R¹ and —R² represents —O—X—R⁸; and the other one of —R¹ and —R²represents —H, —OH, —OCH₃, —OCF₃, —OC₂H₅, —OC₃H₇, —OCH₂CH₂—OCH₃,—OCH₂CH₂—OC₂H₅;

—X— represents —CR¹¹R¹²—, —CR¹¹R¹²—CR¹³R¹⁴—, —CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—,—CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—,—CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—, —(CH₂)_(n)—NH—, —CO—,—(CH₂)_(n)—CO—, —(CH₂)_(n)—NH—CO—NH—, —(CH₂)_(n)—NH—CO—,—(CH₂)_(n)—NH—CO—O—, —(CH₂)_(n)—CO—NR⁹—, —(CH₂)_(n)—O—CO—NH—,—(CH₂)_(n)—O—CO—, —(CH₂)_(n)—O—, —(CH₂)_(n)—;

n is an integer selected from 1, 2, 3, 4, 5 and 6;

—R³, —R⁴, —R⁵, —R⁶ are independently of each other selected from —H,halogen, nitro, C₁₋₄-alkyl, C₃-C₅-cycloalkyl, C₁₋₆-alkoxy;

—R⁸ represents —H, —OH, —F, —Cl, —Br, —I, —OCH₃, —OC₂H₅, —OC₃H₇,—O-cyclo-C₃H₅, —OCH(CH₃)₂, —OC(CH₃)₃, —OC₄H₉, —CHO, —COCH₃, —COC₂H₅,—COC₃H₇, —CO-cyclo-C₃H₅, —COCH(CH₃)₂, —COC(CH₃)₃, —COOH, -cyclo-C₃H₅,-cyclo-C₄H₇, -cyclo-C₅H₉, —COOCH₃, —COOC₂H₅, —COOC₃H₇, —COO-cyclo-C₃H₅,—COOCH(CH₃)₂, —COOC(CH₃)₃, —CONH₂, —CONHCH₃, —CONHC₂H₅, —CONHC₃H₇,—CONH-cyclo-C₃H₅, —CONH[CH(CH₃)₂], —CONH[C(CH₃)₃], —CON(CH₃)₂,—CON(C₂H₅)₂, —CON(C₃H₇)₂, —CON(cyclo-C₃H₅)₂, —CON[CH(CH₃)₂]₂,—CON[C(CH₃)₃]₂, —NH₂, —NHCH₃, —NHC₂H₅, —NHC₃H₇, —NH-cyclo-C₃H₅,—NHCH(CH₃)₂, —NHC(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(C₃H₇)₂,—N(cyclo-C₃H₅)₂, —N[CH(CH₃)₂]₂, —N[C(CH₃)₃]₂, —OOC—CH₃, —OOC—C₂H₅,—OOC—C₃H₇, —OOC-cyclo-C₃H₅, —OOC—CH(CH₃)₂, —OOC—C(CH₃)₃, —NH—CO—NH₂,—NH—CO—NHCH₃, —NH—CO—NHC₂H₅, —NH—CO—NHC₃H₇, —NH—CO—NH-cyclo-C₃H₅,—NH—CO—NH[CH(CH₃)₂], —NH—CO—NH[C(CH₃)₃], —NH—CO—N(CH₃)₂,—NH—CO—N(C₂H₅)₂, —NH—CO—N(C₃H₇)₂, —NH—CO—N(cyclo-C₃H₅)₂,—NH—CO—N[CH(CH₃)₂]₂, —NH—CO—N[C(CH₃)₃]₂, —NH—COOCH₃, —NH—COOC₂H₅,—NH—COOC₃H₇, —NH—COO-cyclo-C₃H₅, —NH—COOCH(CH₃)₂, —NH—COOC(CH₃)₃,—O—CO—NH₂, —O—CO—NHCH₃, —O—CO—NHC₂H₅, —O—CO—NHC₃H₇, —O—CO—NH-cyclo-C₃H₅,—O—CO—NH[CH(CH₃)₂], —O—CO—NH[C(CH₃)₃], —O—CO—N(CH₃)₂, —O—CO—N(C₂H₅)₂,—O—CO—N(C₃H₇)₂, —O—CO—N(cyclo-C₃H₅)₂, —O—CO—N[CH(CH₃)₂]₂,—O—CO—N[C(CH₃)₃]₂, —NH—CO—NR⁹R¹⁰, —CO—NR⁹R¹⁰, —NR⁹R¹⁰, —CH₂F—CHF₂, —CF₃,—CH₂Br, —CH₂—CH₂F, —CH₂—CH₂Cl, —CH₂—CH₂Br, —CH₃, —C₂H₅, —C₃H₇,—CH(CH₃)₂, —C(CH₃)₃, —C₄H₉, —C₅H₁₁, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅,—C(CH₃)₃, -Ph, —CH₂-Ph, —CH═CH₂, —CH₂—CH═CH₂, —C≡CH,

—R⁹ and —R¹⁹ are independently of each other selected from —H,—CH₂F—CHF₂, —CF₃, —CH₂Cl, —CH₂Br, —CH₂—CH₂F, —CH₂—CH₂Cl, —CH₂—CH₂Br,—CH₃, —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C(CH₃)₃, —C₄H₉, —O₅H₁₁, —CH₂—CH(CH₃)₂,—CH(CH₃)—C₂H₅, —C(CH₃)₃, -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉,-cyclo-C₆H₁₁;—R⁷ represents one of the following groups —CH₃, —C₂H₅, —C₃H₇,

R¹¹— R²⁷ represent independently of each other —H, —OH, —OCH₃, —OC₂H₅,—OC₃H₇, —O-cyclo-C₃H₅, —OCH(CH₃)₂, —OC(CH₃)₃, —OC₄H₉, —OCH₂Ph, —OPh,—SH, —SCH₃, —SC₂H₅, —NO₂, —F, —Cl, —Br, —I, —CN, —CHO, —COCH₃, —COC₂H₅,—COC₃H₇, —CO-cyclo-C₃H₅, —COCH(CH₃)₂, —COON, —COOCH₃, —COOC₂H₅,—COOC₃H₇, —COO-cyclo-C₃H₅, —COOCH(CH₃)₂, —OOC—CH₃, —OOC—C₂H₅, —OOC—C₃H₇,—OOC-cyclo-C₃H₅, —OOC—CH(CH₃)₂, —CONH₂, —CONHCH₃, —CONHC₂H₅, —CONHC₃H₇,—CONH-cyclo-C₃H₅, —CONH[CH(CH₃)₂], —CON(CH₃)₂, —CON(C₂H₅)₂, —CON(C₃H₇)₂,—CON(cyclo-C₃H₅)₂, —NH—OC—CH₃, —NH—OC—C₂H₅, —NH—OC—C₃H₇,—NH—OC-cyclo-C₃H₅, —NH—OC—CH(CH₃)₂, —NH—OC—C(CH₃)₃, —NH₂, —NHCH₃,—NHC₂H₅, —NHC₃H₇, —NH-cyclo-C₃H₅, —NHCH(CH₃)₂, —N(CH₃)₂, —N(C₂H₅)₂,—N(C₃H₇)₂, —N(cyclo-C₃H₅)₂, —N[CH(CH₃)₂]₂, —SOCH₃, —SOC₂H₅, —SO₂CH₃,—SO₂C₂H₅, —SO₃H, —SO₃CH₃, —SO₃C₂H₅, —SO₃C₃H₇, —OCF₃, —OC₂F₅,—OCH₂F—OCHF₂, —CH₂F—CHF₂, —CF₃, —CH₂Cl, —CH₂Br, —CH₂—CH₂F, —CH₂—CH₂Cl,—CH₃, —C₂H₅, —C₃H₇, -cyclo-C₃H₅, —CH(CH₃)₂, —C(CH₃)₃, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —CH═CH₂, —CH₂—CH═CH₂,—CH═CH—CH₃, —C≡CH, —C≡C—CH₃, —CH₂—C≡CH, -Ph, —CH₂-Ph, —CH═CH-Ph;

and stereoisomeric forms, solvates, hydrates and/or pharmaceuticallyacceptable salts thereof.

If —R¹ is —O—X—R⁸, —R² is preferably —H, —OCH₃, —OCF₃, —OC₂H₅ and if —R²is —O—X—R⁸, than —R¹ is preferably —H, —OCH₃, —OCF₃, —OC₂H₅.

Preferably —R³, —R⁴, —R⁵, —R⁶ are independently of each —OCH₃, —OC₂H₅,—OC₃H₇, —OCF₃, —F, —Cl, —Br, —I, —CH₃, —C₂H₅, —C₃H₇, -cyclo-C₃H₅,—CH(CH₃)₂, and more preferably —OCH₃, —OC₂H₅, —OCF₃, —F, —Cl, —Br, —CH₃,—C₂H₅. Moreover it is preferred if at least one of —R³, —R⁴ and —R⁵ areselected from —F or —Cl. It is also preferred if at least one of —R³ and—R⁴ is —F and preferably —R³ is —F.

Preferably —R⁷ is one of the following groups —CH₃, —C₂H₅, —C₃H₇, —C₄H₉,—C₅H₁₁,

—R⁸ represents preferably

Compounds wherein R¹ and R² are a methoxy group are excluded from thepresent application. Such compounds having the substitution pattern ofthe compounds disclosed herein have shown moderate to low activity or noactivity and are consequently not preferred. Also compounds of generalformula (I), wherein both groups R¹ and R² are ethoxy groups are stillnot preferred and could also be excluded from the present invention.However compounds wherein both of R¹ and R² represent propoxy, butoxy,pentoxy etc. have shown activity and belong to the compounds of thepresent invention and are consequently not excluded from the scope ofprotection.

Excluded from this application and excluded from the patent claims andexcluded from the general formula (I) are the following compounds whichare excluded by the following disclaimer:

-   N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-methyl-N-(2-phenylethyl)sulfamide,-   N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-1-phenylmethanesulfonamide,-   N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-2-phenylethanesulfonamide,-   N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-phenylpropane-1-sulfonamide.

The following specific compounds are also preferred which are selectedfrom the group comprising or consisting of:

-   1)    2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   2)    2-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   3)    4-Chloro-2-fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   4)    N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethyl-benzenesulfonamide,-   5)    N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-trifluoromethyl-benzenesulfonamide,-   6)    2,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   7)    N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-nitro-benzenesulfonamide,-   8) Biphenyl-3-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-loxy]-phenyl}-amide,-   9)    3-Difluoromethoxy-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   10)    N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenoxy-benzenesulfonamide,-   11)    2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   12)    2,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   13) Biphenyl-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   14)    N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-phenoxy-benzenesulfonamide,-   15)    2-Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   16)    2,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   17)    2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   18)    4-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-methoxy-benzenesulfonamide,-   19)    2-Bromo-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   20)    2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   21)    N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-nitro-benzenesulfonamide,-   22)    3-Fluoro-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   23)    3-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   24)    N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,-   25)    N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide,-   26)    2-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   27)    4-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   28)    N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methyl-benzenesulfonamide,-   29)    2-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   30)    3-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   31) Thiophene-2-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)amide,-   32)    2,6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   33)    N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,-   34)    3,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide,-   35)    3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide.-   36)    N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   37)    3-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   38)    2-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   39)    ′N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-trifluoromethyl-benzenesulfonamide-   40)    N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-nitro-benzenesulfonamide-   41)    3-Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   42)    N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-methoxy-benzenesulfonamide,-   43)    3-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   44)    N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methyl-benzenesulfonamide,-   45)    N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide,-   46)    N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-trifluoromethoxy-benzenesulfonamide,-   47)    2,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   48)    3,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   49)    2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   50)    2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin)-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   51)    2,6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   52)    3,4-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   53)    3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   54)    3-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   55)    2-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-5-methyl-benzenesulfonamide,-   56)    3-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-4-methyl-benzenesulfonamide,-   57)    3-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   58) Naphthalene-1-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   59)    N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-phenoxy-benzenesulfonamide,-   60) Cyclopropanesulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   61) 1-Methyl-1H-pyrazole-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   62) 5-Methyl-thiophene-2-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   63) 5-Chloro-thiophene-2-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   64) 2,4-Dichloro-thiophene-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   65) Thiophene-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   66)    3-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic    acid methyl ester,-   67) Benzo[b]thiophene-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   68) 1-Ethyl-1H-pyrazole-4-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   69)    3-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   70)    N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-methyl-benzenesulfonamide,-   71)    N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,-   72)    3-Cyano-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   73) 2-Phenyl-ethenesulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   74) Quinoline-8-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,-   75)    3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,-   76)    3,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide,-   77)    2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   78)    N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethoxy-benzenesulfonamide,-   79) Butane-1-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide,-   80)    2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(piperidin-3-ylmethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   81)    2-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   82)    2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   83)    2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   84)    2,5-Difluoro-N-{3-fluoro-4-[7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide,-   85)    N-(3-Fluoro-4-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,-   86)    N-(3-Fluoro-4-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy}-quinolin-4-yloxy]-phenyl)-2-trifluoromethyl-benzenesulfonamide,-   87)    N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,-   88)    N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide,-   89)    N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-2-trifluoromethyl-benzenesulfonamide,-   90)    2,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,-   91)    N-{4-[6,7-Bis-(2-methoxy-ethoxy)-quinolin-4-yloxy]-3-fluoro-phenyl}-2,6-difluoro-benzenesulfonamide,-   92)    {4-[2-Fluoro-4-(2-fluoro-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-acetic    acid ethyl ester,-   93)    2-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-N,N-dimethyl-acetamide,-   94) Cyclohexanecarboxylic acid    4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yl    ester,-   95)    N-(3-Fluoro-4-{6-methoxy-7-[3-(tetrahydro-pyran-4-ylamino)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,-   96)    N-{4-[7-(3-Cyclopropylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,-   97)    N-{4-[7-(3-Cyclobutylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,-   98)    N-(4-{7-[3-(3-tert-Butyl-ureido)-propoxy]-6-methoxy-quinolin-4-yloxy}-3-fluoro-phenyl)-2-trifluoromethyl-benzenesulfonamide,-   99)    N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,-   100)    N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,-   101)    N-{-4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,-   102)    N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide.-   103)    N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide-   104)    2,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide-   105) Thiophene-2-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-amide-   106)    2,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide-   107) 1-Methyl-1H-pyrazole-3-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-amide-   108)    2-Chloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide-   109)    N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-2-nitro-benzenesulfonamide-   110)    2,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   111)    N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-fluoro-benzenesulfonamide-   112)    N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide-   113) Benzo[b]thiophene-3-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide-   114) Benzo[b]thiophene-3-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide-   115) Benzo[b]thiophene-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-loxy}-phenyl)-amide-   116) Benzo[b]thiophene-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   117) Benzo[b]thiophene-3-sulfonic acid    (3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   118)    N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide-   119)    2,6-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   120)    (3-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-carbamic    acid tert-butyl ester-   121)    (3-{4-[4-(2,5-Difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-carbamic    acid tert-butyl ester-   122)    N-{4-[7-(3-Amino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,5-difluoro-benzenesulfonamide    hydrochloride-   123)    2,5-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   124)    2,5-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   125)    2,6-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   126)    N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide-   127)    2,5-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   128)    2,6-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   129) Thiophene-2-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   130) 5-Chloro-thiophene-2-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   131) 5-Methyl-thiophene-2-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   132)    N-[5-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-4-methyl-thiazol-2-yl]-acetamide-   133) Thiophene-3-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   134) 2,5-Dichloro-thiophene-3-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   135)    3-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic    acid methyl ester-   136) Benzo[b]thiophene-3-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   137) Furan-2-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   138) 3,5-Dimethyl-isoxazole-4-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   139) 1-Methyl-1H-pyrazole-3-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   140) 1-Ethyl-1H-pyrazole-4-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   141) 2-Methyl-1H-imidazole-4-sulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   142) Cyclopropanesulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   143) 2-Phenyl-ethenesulfonic acid    (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   144) Thiophene-2-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   145) 5-Chloro-thiophene-2-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   146) 2,4-Dichloro-thiophene-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   147) Benzo[b]thiophene-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   148) Furan-2-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   149) 2-Methyl-1H-imidazole-4-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   150) 1-Methyl-1H-pyrazole-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)amide-   151)    2,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   152)    2,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   153)    N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide-   154)    2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   155)    3-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenylsulfamoyl}-thiophene-2-carboxylic    acid methyl ester-   156)    3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic    acid methyl ester-   157)    3-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenylsulfamoyl}-thiophene-2-carboxylic    acid methyl ester-   158)    3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic    acid methyl ester-   159) 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide-   160) 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   161) 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid    (3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl)-amide-   162) 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   163) 1-Methyl-1H-pyrazole-3-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide-   164) 1-Methyl-1H-pyrazole-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   165) 1-Methyl-1H-pyrazole-3-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide-   166) 1-Methyl-1H-pyrazole-3-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   167) 2-Methyl-3H-imidazole-4-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide-   168) 2-Methyl-3H-imidazole-4-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   169) 2-Methyl-3H-imidazole-4-sulfonic acid    {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide-   170) 2-Methyl-3H-imidazole-4-sulfonic acid    (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide-   171)    2,5-Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide-   172)    2,6-Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide-   173)    2,6-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   174)    N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-2-trifluoromethoxy-benzenesulfonamide-   175)    2,5-Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide-   176)    2,6-Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide-   177)    N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,5-difluoro-benzenesulfonamide-   178)    N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,6-difluoro-benzenesulfonamide-   179)    N-{-4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethoxy-benzenesulfonamide-   180)    2,5-Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-benzenesulfonamide-   181)    2,6-Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-benzenesulfonamide-   182) 5-Chloro-thiophene-2-sulfonic acid    {4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-amide-   183)    N-(5-{-4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenylsulfamoyl}-4-methyl-thiazol-2-yl)-acetamide-   184)    3-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenylsulfamoyl}-thiophene-2-carboxylic    acid methyl ester-   185) Furan-2-sulfonic acid    {-4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-amide-   186) Thiophene-2-sulfonic acid    {4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-amide-   187)    2,5-Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   188)    2,6-Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   189)    N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide-   190)    N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide-   191)    2,5-Dichloro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   192)    2,6-Dichloro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   193)    N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide-   194)    N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide-   195)    N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide-   196)    N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide-   197)    2,5-Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   198)    2,6-Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   199)    2,5-Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-benzenesulfonamide-   200)    2,6-Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-benzenesulfonamide-   201)    N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethyl-benzenesulfonamide-   202)    N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethoxy-benzenesulfonamide-   203)    2,5-Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-benzenesulfonamide-   204)    2,6-Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-benzenesulfonamide-   205) Naphthalene-2-sulfonic acid    [3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-amide-   206) Cyclopropanesulfonic acid    [3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-amide-   207)    2,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide-   208)    N-(3-Methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide-   209)    N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide-   210)    N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide-   211) Acetic acid    4-{4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-butyl    ester-   212) Acetic acid    4-{4-[2-fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-butyl    ester-   213)    N-{2-Fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethyl-benzenesulfonamide-   214)    N-{3-Fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethyl-benzenesulfonamide-   215)    N-(2-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

The present invention also comprises pharmaceutically acceptable saltsof the compounds according to the general formula (I), allstereoisomeric forms of the compounds according to the general formula(I) as well as solvates, especially hydrates or prodrugs thereof. Aprodrug is commonly described as an inactive or protected derivative ofan active ingredient or a drug, which is converted to the activeingredient or drug in the body.

In case, the inventive compounds bear basic and/or acidic substituents,they may form salts with organic or inorganic acids or bases. Examplesof suitable acids for such acid addition salt formation are hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid,citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylicacid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleicacid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid,formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid,hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid,p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid,ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid,ethylenesulfonic acid, p-toluenesulfonic acid, naphtholsulfonic acid,sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid,o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid,adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluicacid, naphthylamine sulfonic acid, and other mineral or carboxylic acidswell known to those skilled in the art. The salts are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce a salt in the conventional manner. Examples for suitableinorganic or organic bases are, for example, NaOH, KOH, NH₄OH,tetraalkylammonium hydroxide, lysine or arginine and the like. Salts maybe prepared in a conventional manner using methods well known in theart, for example by treatment of a solution of the compound of thegeneral formula (I) with a solution of an acid, selected out of thegroup mentioned above.

Some of the compounds of the present invention may be crystallised orrecrystallised from solvents such as aqueous and organic solvents. Insuch cases solvates may be formed. This invention includes within itsscope stoichiometric solvates including hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation.

Certain compounds of the general formula (I) may exist in the form ofoptical isomers, e.g. diastereoisomers and mixtures of isomers in allratios, e.g. racemic mixtures. The invention includes all such forms, inparticular the pure isomeric forms. The different isomeric forms may beseparated or resolved one from the other by conventional methods, or anygiven isomer may be obtained by conventional synthetic methods or bystereospecific or asymmetric syntheses. Where a compound according tothe general formula (I) contains an alkene moiety, the alkene can bepresented as a cis or trans isomer or a mixture thereof. When anisomeric form of a compound of the invention is provided substantiallyfree of other isomers, it will preferably contain less than 5% w/w, morepreferably less than 2% w/w and especially less than 1% w/w of the otherisomers.

Another aspect of the present invention relates to the use of theinventive quinolinyloxyphenylsulfonamide derivatives as drugs, i.d. aspharmaceutically active agents applicable in medicine.

The inventive quinolinyloxyphenylsulfonamides are useful for thetreatment and/or prevention of AXL receptor tyrosine kinase induceddisorders, wherein the AXL receptor tyrosine kinase induced disordersare selected from the group comprising hyperproliferative disorders,breast, colon, prostate, lung, gastric, ovarian, endometrial, renal,hepatocellular, thyroid, uterine cancer, esophageal carcinoma, squamouscell carcinoma, leukemia, osteosarcoma, melanoma, glioblastoma, andneuroblastoma.

Moreover the inventive quinolinyloxyphenylsulfonamides are useful forthe preparation of a pharmaceutical formulation for prophylaxis,treatment and after-treatment cancer, tumors and cancer metastases.Thus, the quinolinyloxyphenylsulfonamide compounds of the presentinvention can be used for prophylaxis and treatment of various cancertypes and especially of cancer metastases.

Furthermore, the compounds of the present invention are useful for thetreatment and after-treatment of various cancer types such asadenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma,ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma,pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma,breast cancer, Burkitt's lymphoma, corpus cancer, CUP-syndrome(carcinoma of unknown primary), colorectal cancer, small intestinecancer, small intestinal tumors, ovarian cancer, endometrial carcinoma,ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinaltumors, gastric cancer, gallbladder cancer, gall bladder carcinomas,uterine cancer, cervical cancer, cervix, glioblastomas, gynecologictumors, ear, nose and throat tumors, hematologic neoplasias, hairy cellleukemia, urethral cancer, skin cancer, skin testis cancer, brain tumors(gliomas), brain metastases, testicle cancer, hypophysis tumor,carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bonecancer, colorectal carcinoma, head and neck tumors (tumors of the ear,nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer(cancer in the mouth area and on lips), cancer of the central nervoussystem, liver cancer, liver metastases, leukemia, eyelid tumor, lungcancer, lymph node cancer (Hodgkin's/Non-Hodgkin's), lymphomas, stomachcancer, malignant melanoma, malignant neoplasia, malignant tumorsgastrointestinal tract, breast carcinoma, rectal cancer,medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosisfungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renalcell carcinomas, non-Hodgkin's lymphomas, oligodendroglioma, esophagealcarcinoma, osteolytic carcinomas and osteoplastic carcinomas,osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer,plasmocytoma, prostate cancer, pharyngeal cancer, rectal carcinoma,retinoblastoma, vaginal cancer, thyroid carcinoma, Schneeberger disease,esophageal cancer, spinalioms, T-cell lymphoma (mycosis fungoides),thymoma, tube carcinoma, eye tumors, urethral cancer, urologic tumors,urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors,soft tissue sarcoma, Wilm's tumor, cervical carcinoma and tongue cancer.

Most active are the inventive compounds on lung cancer, lymph nodecancer (Hodgkin's/Non-Hodgkin's), head and neck tumors (tumors of theear, nose and throat area), breast cancer, ovarian cancer, gastriccancer, gastrointestinal tumors, intestinal tumors.

Another aspect of the present invention is directed to the use of atleast one quinolinyloxyphenylsulfonamide compound and/orpharmaceutically acceptable salts thereof for the preparation of apharmaceutical formulation for prophylaxis, treatment and/orafter-treatment of cancer, tumors and especially cancer metastases.

Still another aspect of the present invention is directed topharmaceutical compositions comprising at least onequinolinyloxyphenylsulfonamide compound of the present invention asactive ingredient, together with at least one pharmaceuticallyacceptable carrier, excipient and/or diluents. The pharmaceuticalcompositions of the present invention can be prepared in a conventionalsolid or liquid carrier or diluent and a conventionalpharmaceutically-made adjuvant at suitable dosage level in a known way.The preferred preparations are adapted for oral application. Theseadministration forms include, for example, pills, tablets, film tablets,coated tablets, capsules, powders and deposits.

Furthermore, the present invention also includes pharmaceuticalpreparations for parenteral application, including dermal, intradermal,intragastral, intracutan, intravasal, intravenous, intramuscular,intraperitoneal, intranasal, intravaginal, intrabuccal, percutan,rectal, subcutaneous, sublingual, topical, or transdermal application,which preparations in addition to typical vehicles and/or diluentscontain at least one compound according to the present invention and/ora pharmaceutical acceptable salt thereof as active ingredient.

The pharmaceutical compositions according to the present inventioncontaining at least one compound according to the present invention,and/or a pharmaceutical acceptable salt thereof as active ingredientwill typically be administered together with suitable carrier materialsselected with respect to the intended form of administration, i.e. fororal administration in the form of tablets, capsules (either solidfilled, semi-solid filled or liquid filled), powders for constitution,extrudates, deposits, gels, elixirs, dispersable granules, syrups,suspensions, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of tablets or capsules, the active drug component may be combinedwith any oral non-toxic pharmaceutically acceptable carrier, preferablywith an inert carrier like lactose, starch, sucrose, cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, talc,mannitol, ethyl alcohol (liquid filled capsules) and the like. Moreover,suitable binders, lubricants, disintegrating agents and coloring agentsmay also be incorporated into the tablet or capsule. Powders and tabletsmay contain about 5 to about 95 weight % of thequinolinyloxyphenylsulfonamide compound and/or the respectivepharmaceutically active salt as active ingredient.

Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol and waxes. Among suitablelubricants there may be mentioned boric acid, sodium benzoate, sodiumacetate, sodium chloride, and the like. Suitable disintegrants includestarch, methylcellulose, guar gum, and the like. Sweetening andflavoring agents as well as preservatives may also be included, whereappropriate. The disintegrants, diluents, lubricants, binders etc. arediscussed in more detail below.

Moreover, the pharmaceutical compositions of the present invention maybe formulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimise the therapeutic effect(s), e.g. antihistaminic activity and thelike. Suitable dosage forms for sustained release include tablets havinglayers of varying disintegration rates or controlled release polymericmatrices impregnated with the active components and shaped in tabletform or capsules containing such impregnated or encapsulated porouspolymeric matrices.

Liquid form preparations include solutions, suspensions, and emulsions.As an example, there may be mentioned water or water/propylene glycolsolutions for parenteral injections or addition of sweeteners andopacifiers for oral solutions, suspensions, and emulsions. Liquid formpreparations may also include solutions for intranasal administration.Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be present in combination with apharmaceutically acceptable carrier such as an inert, compressed gas,e.g. nitrogen. For preparing suppositories, a low melting fat or wax,such as a mixture of fatty acid glycerides like cocoa butter is meltedfirst, and the active ingredient is then dispersed homogeneously thereine.g. by stirring. The molten, homogeneous mixture is then poured intoconveniently sized moulds, allowed to cool, and thereby solidified.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions, and emulsions.

The compounds according to the present invention may also be deliveredtransdermally. The transdermal compositions may have the form of acream, a lotion, an aerosol and/or an emulsion and may be included in atransdermal patch of the matrix or reservoir type as is known in the artfor this purpose.

The term capsule as recited herein refers to a specific container orenclosure made e.g. of methyl cellulose, polyvinyl alcohols, ordenatured gelatins or starch for holding or containing compositionscomprising the active ingredient(s). Capsules with hard shells aretypically made of blended of relatively high gel strength gelatins frombones or pork skin. The capsule itself may contain small amounts ofdyes, opaquing agents, plasticizers and/or preservatives. Under tablet acompressed or moulded solid dosage form is understood which comprisesthe active ingredients with suitable diluents. The tablet may beprepared by compression of mixtures or granulations obtained by wetgranulation, dry granulation, or by compaction well known to a person ofordinary skill in the art.

Oral gels refer to the active ingredients dispersed or solubilised in ahydrophilic semi-solid matrix. Powders for constitution refers to powderblends containing the active ingredients and suitable diluents which canbe suspended e.g. in water or in juice.

Suitable diluents are substances that usually make up the major portionof the composition or dosage form. Suitable diluents include sugars suchas lactose, sucrose, mannitol, and sorbitol, starches derived fromwheat, corn rice, and potato, and celluloses such as microcrystallinecellulose. The amount of diluent in the composition can range from about5 to about 95% by weight of the total composition, preferably from about25 to about 75 weight %, and more preferably from about 30 to about 60weight %.

The term disintegrants refers to materials added to the composition tosupport break apart (disintegrate) and release the pharmaceuticallyactive ingredients of a medicament. Suitable disintegrants includestarches, “cold water soluble” modified starches such as sodiumcarboxymethyl starch, natural and synthetic gums such as locust bean,karaya, guar, tragacanth and agar, cellulose derivatives such asmethylcellulose and sodium carboxymethylcellulose, microcrystallinecelluloses, and cross-linked microcrystalline celluloses such as sodiumcroscarmellose, alginates such as alginic acid and sodium alginate,clays such as bentonites, and effervescent mixtures. The amount ofdisintegrant in the composition may range from about 2 to about 20weight % of the composition, more preferably from about 5 to about 10weight %.

Binders are substances which bind or “glue” together powder particlesand make them cohesive by forming granules, thus serving as the“adhesive” in the formulation. Binders add cohesive strength alreadyavailable in the diluent or bulking agent. Suitable binders includesugars such as sucrose, starches derived from wheat corn rice andpotato, natural gums such as acacia, gelatin and tragacanth, derivativesof seaweed such as alginic acid, sodium alginate and ammonium calciumalginate, cellulose materials such as methylcellulose, sodiumcarboxymethylcellulose and hydroxypropylmethylcellulose,polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminumsilicate. The amount of binder in the composition may range from about 2to about 20 weight % of the composition, preferably from about 3 toabout 10 weight %, and more preferably from about 3 to about 6 weight %.

Lubricants refer to a class of substances which are added to the dosageform to enable the tablet granules etc. after being compressed torelease from the mould or die by reducing friction or wear. Suitablelubricants include metallic stearates such as magnesium stearate,calcium stearate, or potassium stearate, stearic acid, high meltingpoint waxes, and other water soluble lubricants such as sodium chloride,sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols andD,L-leucine. Lubricants are usually added at the very last step beforecompression, since they must be present at the surface of the granules.The amount of lubricant in the composition may range from about 0.2 toabout 5 weight % of the composition, preferably from about 0.5 to about2 weight %, and more preferably from about 0.3 to about 1.5 weight % ofthe composition.

Glidents are materials that prevent caking of the components of thepharmaceutical composition and improve the flow characteristics ofgranulate so that flow is smooth and uniform. Suitable glidents includesilicon dioxide and talc. The amount of glident in the composition mayrange from about 0.1 to about 5 weight % of the final composition,preferably from about 0.5 to about 2 weight %.

Coloring agents are excipients that provide coloration to thecomposition or the dosage form. Such excipients can include food gradedyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.The amount of the coloring agent may vary from about 0.1 to about 5weight % of the composition, preferably from about 0.1 to about 1 weight%.

EXPERIMENTAL PART Examples

1) Analytical Methods (HPLC, NMR, TLC and Melting Point)

Analytical HPLC/MS was performed on an Waters HPLC/MS system usingreverse phase

-   -   Method A: Waters XTerra MS C18 (5 cm×4.6 mm, 5 um), gradient        0-95% B (0.00 min 5% B, 0.50 min 5% B, 5.50 min 95% B, 6.00 min        95% B, 6.50 min 5% B, 7.00 min 5% B), Solvent A: Water/0.05%        HCOOH, Solvent B: AcCN/0.05% HCOOH over 7.00 min, flow=2.0        ml/min. Separation module was Waters Alliance 2795.    -   Method B: Waters X Waters XBridge C18 (5 cm×4.6 mm, 3.5 um),        gradient 0-95% B (0.00 min 5% B, 0.50 min 5% B, 5.50 min 95% B,        6.00 min 95%

B, 6.50 min 5% B, 7.00 min 5% B), Solvent A: 5 mM NH₄HCO₃, Solvent B:AcCN over 7.00 min, flow=2.0 ml/min. Separation module was WatersAlliance 2795.

UV spectra were recorded using a Waters 996 DAD UV detector. Massspectra were obtained using Waters SQD MS detector (Ionization: ES⁺/ES⁻,Source block temp: 110 C, Desolvation temp: 250° C., Desolvation Gas:500 L/h, Cone Gas: 80 L/h, Capillary: 3000 V, Cone: 30 V, Extractor: 6V, Rf Lens: 0.1 V, Scan: 80 to 1000 m/z in 1 sec., Inter-scan delay: 0.1s).

¹H NMR spectra were recorded on a Bruker Avanve 300 MHz AV spectrometerin deuterated solvents (DMSO-d₆). Chemical shifts □ are in parts permillion (ppm).

Thin-layer chromatography (TLC) analysis was performed with Kieselgel 60F254 (Merck) plates and visualized using UV light.

Melting point measurement was Büchi melting Point B-54 instrument.

Synthesis of Compounds

First of all general methods will be presented for the synthesis ofbasic building blocks. In subsequent reactions these basic buildingblocks can be functionalized via common methods of organic syntheses toobtain the desired target compounds.

General Method 1 Starting from 4-Hydroxy-Acetophenone Derivatives

R² has the meanings as disclosed herein and is, for instance, —OCH₃.

Synthesis of 1-(4-Benzyloxy-3-methoxy-phenyl)-ethanone[A]

The mixture of 31.62 g (190 mmol)1-(4-hydroxy-3-methoxy-phenyl)-ethanone, 16.36 g (118 mmol) potassiumcarbonate, 0.5 g potassium iodide, 400 ml acetone and 33.15 g (190 mmol)ml benzyl bromide were refluxed for 2 days. The solvent was evaporated,the residue was taken up in 400 ml of water. The precipitate wasfiltered, washed with 100 ml of sodium carbonate saturated aqueoussolution and 2×100 ml of water, then dried on air to give 47.8 g ofproduct [A]. Yield 98%.

Synthesis of 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone [B]

1-(4-Benzyloxy-3-methoxy-phenyl)-ethanone (24.61 g, 96 mmol) wasdissolved in acetic acid (100 ml) and the mixture was cooled to 10° C.Nitric acid fuming (Fluka ID 84392, 100%, 10 ml, 240 mmol) was addeddropwise to the cooled solution over 2 hours. The reaction mixture wasallowed to come to room temperature and stirred for 16 hours. Thereaction mixture was poured into water (400 ml). The precipitate wasfiltered, washed with water, then taken up in sodium hydrogencarbonatesaturated aqueous solution (300 ml) and stirred for 2 hours. Theprecipitate was filtered, washed with water and dried. The raw productwas recrystallized from ethyl alcohol (1000 ml) to give 18.25 g ofproduct [B]. Yield 65%.

Synthesis of 1-(2-amino-4-benzyloxy-5-methoxy-phenyl)-ethanone [C]

A mixture of 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (11.94 g39.6 mmol), ammonium chloride (13.48 g, 250 mmol), zinc powder (65.39 g,1000 mmol), ethyl alcohol (720 ml) and water (70 ml) was refluxed untilcompletion (5 hours). The mixture was filtered through celite and washedwith hot ethyl alcohol. The filtrate was evaporated in vacuum. Theresidue was taken up in the mixture of chloroform (200 ml), water (200ml) and the pH of this mixture was set to 8 by adding sodium hydroxidesolution. The two layers were separated, the aqueous layer was extractedwith chloroform (2×50 ml). The organic layers were combined, washed withwater and over Na₂SO₄, and concentrated to give 9.25 product [α]. Yield86%.

Synthesis of 7-benzyloxy-6-methoxy-1H-quinolin-4-one [D]

A mixture of sodium methylate (270 mmol, 14.75 g, favorable preparedfrom sodium metal and methanol before use), 1,2-dimethoxyethane (122 ml)and 1-(2-amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (6.68 g 24 mmol)was stirred at 0° C. for 1 hour. Ethyl formate (10.7 ml, 9.81 g, 132mmol) was added to the reaction mixture, that was allowed to come toroom temperature and stirred for further 4 hours. The mixture wasdiluted with water (50 ml) and acidified to pH 1 by adding hydrochloricacid (1N, 185 ml). The precipitate was filtered, washed with water anddried to give 6.51 g of product [D]. Yield: 94%.

Synthesis of 7-benzyloxy-4-chloro-6-methoxy-quinoline [E]

A mixture of 7-benzyloxy-6-methoxy-4-quinolone (9.72 g 34.5 mmol) andphosphorus oxychloride (130 ml) was stirred at 110° C. for 3 hours. Thestirred mixture was concentrated at atmospheric pressure. The residuewas dissolved in chloroform (150 ml), then ice and water was added tothe solution. The mixture was rendered weakly alkaline by the additionof saturated sodium carbonate solution. The two phases were separated,the aqueous layer was extracted with chloroform. The extract was washedwith water, dried over sodium sulfate, and the solvent was removed byevaporation under the reduced pressure. The residue was solidified underdiisopropyl ether to give 9.82 g of product [E]. Yield: 94%.

Synthesis of7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline [F]

A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinoline (2.04 g, 6.8mmol), 2-fluoro-4-nitrophenol (2.34 g 14.9 mmol) and chlorobenzene (40ml) was stirred at reflux temperature for 2 days. The reaction mixturewas cooled, diluted with saturated sodium carbonate solution (30 ml) andstirred for 3 hours. The precipitate was filtered and the filtrate wasseparated. The aqueous layer was extracted with chloroform (3×30 ml).The organic layers were combined, washed with water and dried oversodium sulfate. The solvent was removed by evaporation under the reducedpressure. The residue was purified by column chromatography. The pureproduct was solidified under diisopropyl ether to give 1.11 g of product[F]. Yield: 39%.

Synthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol [G]

7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (2.75 g,6.54 mmol) was added slowly in portion into hydrobromic acid solution(33% in acetic acid, 45 ml). The mixture was stirred at room temperaturefor 2 hours, then poured into diethyl ether (300 ml). The precipitatewas filtered and washed with diethyl ether. The solid hydrobromide saltwas stirred in the mixture of sodium acetate aqueous solution (10%, 60ml) and ethyl acetate (15 ml) for 1 day. The precipitate was filtered,washed with water and dried to give 1.82 g of product [G]. Yield: 86%

The free hydroxy group of compound [G] was substituted with the residueR⁸—X— by an etherification reaction or a nucleophilic substitution toresult in compound [H]. For the coupling, for reagent could be usedchloroalkyl-(Cl—X—R⁸), bromoallyl (Br—X—R⁸) or mesylate (MeSO₂—X—R⁸)derivatives as well.

Alternatively, the preparation of compound H can be prepared with ananother method. Some potential intermediate—H-1, H-2, H-3—are describedin the literature that can be used for preparing the corresponding Hcompound, see J. Med. Chem. 2008, 51 (18), 5766-5779 (Noel D. Angelo et.Al.).

The nitro group of compound [H] was reduced to the amino group asdescribed above for compound [C]. The preparation of the sulfonamidegroup is described below.

General Method Starting from 3-Hydroxy-Acetophenone Derivatives

R¹ has the meanings as disclosed herein and is, for instance, —OCH₃.

The D′ compound can be prepared in the similar manner as described inthe patent US 2005/0029264, Example 13 (Atsushi Miwa et al.).

General Method 2 Starting from Aniline Derivatives

R² has the meanings as disclosed herein and is, for instance, —OCH₃.

For some embodiments, compounds, showed in Reaction Scheme can beprepared according to the described literature. For example thepreparation of compound D (where R² is a hydrogen atom) is described inthe patent WO 2005/032484, Example 1 (Lindstrom Kyle et al.).

In certain embodiments, benzyloxy group is at the position 6 in thequinoline ring and can be prepared in the similar manner [WO2005/032484, Example 2 (Lindstrom Kyle et al.)]:

General Procedure for Sulfonamide Compounds

0.31 mmol appropriately substituted sulfonylchloride and 0.3 mmolappropriately substituted 4-(4-amino-phenoxy)quinoline derivative wasdissolved 3 ml abs. pyridine and stirred while the starting aminedisappears according to the TLC (at room temperature 1-21 days or at 60°C. for 24 hours). The reaction mixture was poured into 50 ml of waterand extracted with 3×30 ml of chloroform. The organic phase was washedwith water, dried over anhydrous sodium sulfate, filtrated andevaporated. The residue was purified on TLC plate (saturated with vapourof NH₄OH, eluent chloroform-methanol 9:1). The pure product wassolidified under diisopropyl ether.

General Procedure for Modification of Sulfonamide Compounds

There are some other possibilities to modify the sulfonamidederivatives. For example using a protected aminoalkyl reagent we couldprepare the protected derivative [G+3]. After removing the protectivegroup the free amine [G+4] can be prepared, which is convenient materialfor produce further derivatives, e.g. react with isocyanate or withaldehyde or ketone (reductive alkylation).

The synthesis is equivalent to the above reaction scheme for theseinventive compounds wherein R² represents R⁸—X—. The general reactionscheme is shown below. The single reaction protocols are the same asdisclosed above.

Example 12,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₃₀H₃₀F₃N₃O₅S Mw. 601.65

LC/MS purity: 99%, m/z 600[M−H]⁻, 602 [M+H]⁺ Rt. 3.12 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.0 (bs, 1H), 8.41 (d, 1H), 7.61-7.03 (m,8H), 6.30 (d, 1H), 4.26 (t, 2H), 3.97 (s, 3H), 3.40 (bs, 2H), 3.33 (bs,2H), 2.45 (bs, 2H), 2.11 (bs, 6H), 1.63 (bs, 2H).

Melting point: 206-208° C.

Yield: 46%

Example 22-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₃₀H₃₁F₂N₃O₅S Mw. 583.66

LC/MS purity: 99%, m/z 582 [M−H]⁻¹, 584 [M+H]⁺ Rt. 3.18 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.2 (bs, 1H), 8.43 (d, 1H), 7.84 (t, 1H),7.60 (d, 1H), 7.47 (s, 1H), 7.32 (m, 3H), 7.18 (t, 1H), 6.99 (d, 1H),6.87 (d, 1H), 6.33 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.43 (bs, 6H),1.96 (t, 2H), 1.52 (bs, 4H), 1.40 (bs, 2H).

Melting point: 214-216° C.

Yield: 38%

Example 34-Chloro-2-fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₃₀H₃₀ClF₂N₃O₅S Mw. 618.10

LC/MS purity: 100%, m/z 616 [M−H]⁻, 618 [M+H]⁺ Rt. 3.32 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.8 (bs, 1H), 8.43 (d, 1H), 7.82 (t, 1H),7.56 (dd, 1H), 7.49 (s, 1H), 7.39 (m, 2H), 7.15 (t, 1H), 6.96 (dd, 1H),6.82 (d, 1H), 6.35 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 2.58 (m, 6H),2.02 (m, 2H), 1.56 (m, 4H), 1.43 (m, 2H).

Melting point: 122-124° C.

Yield: 36%

Example 4N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethyl-benzenesulfonamide

C31H31F4N3O5S Mw. 633.67

LC/MS purity: 100%, m/z 632 [M−H]⁻, 634 [M+H]⁺ Rt. 3.36 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.0 (bs, 1H), 8.45 (d, 1H), 8.14 (d, 1H),7.93 (d, 1H), 7.78 (m, 2H), 7.48 (s, 1H), 7.38 (s, 1H), 7.21 (t, 1H),7.00 (dd, 1H), 6.88 (d, 1H), 6.36 (d, 1H), 4.19 (t, 2H), 3.64 (s, 3H),2.62 (m, 6H), 2.03 (m, 2H), 1.59 (m, 4H), 1.44 (m, 2H).

Melting point: 173-175° C.

Yield: 48

Example 5N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-trifluoromethyl-benzenesulfonamide

C₃₁H₃₁F₄N₃O₅S Mw. 633.67

LC/MS purity: 100%, m/z 632[M−H]⁻, 634 [M+H]⁺ Rt. 3.34 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.8 (bs, 1H), 8.43 (d, 1H), 8.00 (m, 3H),7.78 (t, 2H), 7.48 (s, 1H), 7.38 (s, 1H), 7.22 (t, 1H), 7.04 (dd, 1H),6.89 (d, 1H), 6.32 (d, 1H), 4.19 (t, 1H), 3.92 (s, 3H), 2.64 (m, 6H),2.02 (m, 2H), 1.56 (m, 4H), 1.44 (m, 2H).

Melting point: 123-126° C.

Yield: 61%

Example 62,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₃₀H₃₀Cl₂FN₃O₅S Mw. 634.56

LC/MS purity: 99%, m/z 632 [M−H]⁻, 634 [M+H]⁺ Rt. 3.31 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.8 (bs, 1H), 8.42 (d, 1H), 7.48 (m, 3H),7.37 (m, 2H), 7.08 (t, 1H), 6.90 (d, 1H), 6.73 (d, 1H), 6.33 (d, 1H),4.18 (t, 2H), 3.92 (s, 3H), 2.52 (m, 6H), 1.99 (m, 2H), 1.53 (m, 4H),1.41 (m, 2H).

Melting point: 206-208° C.

Yield: 35%

Example 7N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-nitro-benzenesulfonamide

C₃₀H₃₁FN₄O₇S Mw. 610.67

LC/MS purity: 100%, m/z 609 [M−H]⁻, 611 [M+H]⁺ Rt. 2.99 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.43 (d, 1H), 7.93 (t, 1H), 7.65(m, 3H), 7.49 (s, 1H), 7.38 (s, 1H), 7.06 (t, 1H), 6.84 (dd, 1H), 6.72(d, 1H), 6.35 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H), 2.71 (bs, 6H), 2.07(m, 2H), 1.60 (bs, 4H), 1.46 (bs, 2H).

Melting point: 113-116° C.

Yield: 41%

Example 8

Biphenyl-3-sulfonic acid{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-loxy]-phenyl}-amide

C₃₆H₃₆FN₃O₅S Mw. 641.77

LC/MS purity: 100%, m/z 640 [M−H]⁻, 642 [M+H]⁺ Rt. 3.95 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.37 (d, 1H), 8.03 (s, 1H),7.95 (d, 1H), 7.79 (d, 1H), 7.68 (m, 3H), 7.49 (m, 4H), 7.37 (s, 1H),7.32 (t, 1H), 7.16 (dd, 1H), 7.00 (d, 1H), 6.28 (d, 1H), 4.17 (t, 2H),3.90 (s, 3H), 2.44 (bs, 6H), 1.97 (m, 2H), 1.53 (bs, 4H), 1.39 (m, 2H).

Melting point: 113-115° C.

Yield: 47%

Example 93-Difluoromethoxy-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₃₁H₃₂F₃N₃O₆S Mw. 631.68

LC/MS purity: 100%, m/z 630 [M−H]⁻, 632 [M+H]⁺ Rt. 3.44 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.43 (d, 1H), 8.66-7.21 (m,7H), 7.05 (d, 1H), 6.91 (d, 1H), 6.33 (d, 1H), 4.18 (t, 2H), 3.92 (s,3H), 3.59 (m, 1H), 2.52 (bs, 6H), 1.99 (m, 2H), 1.52 (bs, 4H), 1.41 (m,2H).

Melting point: 105-106° C.

Yield: 77%

Example 10N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenoxy-benzenesulfonamide

C₃₆H₃₆FN₃O₆S Mw. 657.77

LC/MS purity: 97%, m/z 656 [M−H]⁻, 658 [M+H]⁺ Rt. 3.93 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.43 (d, 1H), 7.58-7.24 (m,10H), 7.07-6.90 (m, 4H), 6.35 (d, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 2.49(bs, 6H), 1.99 (bs, 2H), 1.53 (bs, 4H), 1.41 (bs, 2H).

Melting point: 146-147° C.

Yield: 38%

Example 112,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₃₀H₃₀F₃N₃O₅S Mw. 601.65

LC/MS purity: 98%, m/z 600 [M−H]⁻, 602 [M+H]⁺ Rt. 2.99 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 7.59 (t, 1H),7.49 (s, 1H), 7.39 (s, 1H), 7.20 (m, 3H), 7.04 (d, 1H), 6.89 (d, 1H),6.35 (d, 1H), 4.20 (t, 2H), 3.92 (s, 3H), 2.70 (bs, 6H), 2.06 (bs, 2H),1.45 (bs, 4H), 1.24 (bs, 2H).

Melting point: 242-244° C.

Yield: 27%

Example 122,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₁F₃N₄O₅S Mw. 616.66

LC/MS purity: 99%, m/z 615[M−H]⁻, 617 [M+H]⁺ Rt. 2.91 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.43 (d, 1H), 7.60 (m, 1H),7.42 (m, 4H), 7.19 (t, 1H), 7.02 (dd, 1H), 6.88 (d, 1H), 6.35 (d, 1H),4.18 (t, 2H), 4.01 (bs, 4H), 3.92 (s, 3H), 3.35 (bs, 6H), 2.26 (s, 3H),1.95 (m, 2H).

Melting point: 124-126° C.

Yield: 24%

Example 13 Biphenyl-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₆H₃₇FN₄O₅S Mw. 656.78

LC/MS purity: 97%, m/z 655 [M−H]⁻, 657 [M+H]⁺ Rt. 3.71 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.36 (d, 1H), 8.03 (d, 1H),7.96 (t, 1H), 7.79 (d, 1H), 7.67 (m, 3H), 7.52-7.12 (m, 6H), 7.04 (dd,1H), 6.90 (d, 1H), 6.28 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.40 (bs,10H), 2.19 (s, 3H), 1.96 (t, 2H).

Melting point: 190-191° C.

Yield: 40%

Example 14N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-phenoxy-benzenesulfonamide

C₃₆H₃₇FN₄O₆S Mw. 672.78

LC/MS purity: 97%, m/z 671 [M−H]⁻, 673 [M+H]⁺ Rt. 3.68 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.43 (s, 1H), 7.62-7.23 (m,10H), 7.10-6.92 (m, 4H), 6.35 (d, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 2.47(m, 4H), 2.40 (m, 6H), 2.19 (s, 3H), 1.96 (t, 2H).

Melting point: 140-141° C.

Yield: 24%

Example 152-Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂FN₅O₅S Mw. 605.69

LC/MS purity: 99%, m/z 604[M−H]⁻, 606 [M+H]⁺ Rt. 2.73 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.44 (d, 1H), 7.50 (m, 3H),7.37 (m, 3H), 7.28 (t, 1H), 7.10 (d, 1H), 6.96 (d, 1H), 6.34 (d, 1H),4.17 (t, 2H), 3.92 (s, 3H), 2.44 (m, 4H), 2.36 (m, 6H), 2.16 (s, 3H),1.94 (m, 2H).

Melting point: 109-111° C.

Yield: 22%

Example 162,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₁F₃N₄O₅S Mw. 616.66

LC/MS purity: 99%, m/z 615 [M−H]⁻, 617 [M+H]⁺ Rt. 2.93 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.43 (d, 1H), 7.93 (t, 1H), 7.47(m, 2H), 7.36 (s, 1H), 7.22 (m, 2H), 7.08 (dd, 1H), 6.92 (dd, 1H), 6.34(d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.44 (m, 4H), 2.36 (m, 6H), 2.18(s, 3H), 1.96 (t, 2H).

Melting point: 99-102° C.

Yield: 42%

Example 172,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₀F₄N₄O₅S Mw. 634.65

LC/MS purity: 98%, m/z 633[M−H]⁻, 635 [M+H]⁺ Rt. 2.98 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 7.92 (d, 1H),7.80 (d, 1H), 7.77 (t, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.26 (t, 1H),7.02 (d, 1H), 6.36 (d, 1H), 4.21 (t, 2H), 3.98 (s, 3H), 2.45 (m, 4H),2.36 (m, 6H), 2.18 (s, 3H), 1.95 (t, 2H).

Melting point: 88-90° C.

Yield: 45%

Example 184-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-methoxy-benzenesulfonamide

C₃₁H₃₄F₂N₄O₆S Mw. 628.70

LC/MS purity: 99%, m/z 627 [M−H]⁻, 629 [M+H]⁺ Rt. 3.19 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.9 (bs, 1H), 8.44 (d, 1H), 7.52-7.28 (m,6H), 7.10 (d, 1H), 6.94 (dd, 1H), 6.34 (d, 1H), 4.17 (t, 2H), 3.92 (s,3H), 3.88 (s, 3H), 2.44 (m, 4H), 2.37 (m, 6H), 2.19 (s, 3H), 1.94 (t,2H).

Melting point: 167-169° C.

Yield: 60%

Example 192-Bromo-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₂BrFN₄O₅S Mw. 659.58

LC/MS purity: 98%, m/z 657 [M−H]⁻, 659 [M+H]⁺ Rt. 3.17 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.43 (d, 1H), 8.11 (d, 1H),7.81 (d, 1H), 7.57-7.46 (m, 3H), 7.36 (s, 1H), 7.26 (t, 1H), 7.05 (d,1H), 6.94 (d, 1H), 6.34 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.45 (bs,10H), 2.20 (s, 3H), 1.95 (t, 2H).

Melting point: 98-101° C.

Yield: 40%

Example 202,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₁Cl₂FN₄O₅S Mw. 649.57

LC/MS purity: 98%, m/z 647 [M−H]⁻, 649 [M+H]⁺ Rt. 3.20 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.42 (d, 1H), 7.98 (bs, 1H),7.60 (bs, 2H), 7.48 (bs, 1H), 7.38 (bs, 1H), 7.18 (t, 1H), 6.98 (d, 1H),6.85 (d, 1H), 6.34 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.50 (bs, 10H),2.28 (s, 3H), 1.78 (m, 2H).

Melting point: 134-136° C.

Yield: 38%

Example 21N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}phenyl)-2-nitro-benzenesulfonamide

C₃₀H₃₂FN₅O₇S Mw. 625.68

LC/MS purity: 99%, m/z 624 [M−H]⁻, 626 [M+H]⁺ Rt. 2.81 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.43 (d, 1H), 7.96 (m, 1H),7.77 (m, 1H), 7.70 (m, 2H), 7.48 (s, 1H), 7.37 (s, 1H), 7.15 (t, 1H),6.94 (d, 1H), 6.79 (d, 1H), 6.35 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H),2.73 (m, 4H), 2.54 (m, 6H), 2.35 (s, 3H), 1.98 (m, 2H).

Melting point: 125-128° C.

Yield: 29%

Example 223-Fluoro-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₂F₂N₄O₅S Mw. 598.67

LC/MS purity: 99%, m/z 597 [M−H]⁻, 599 [M+H]⁺ Rt. 3.07 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.9 (bs, 1H), 8.44 (d, 1H), 7.63-7.47 (m,5H), 7.37 (s, 1H), 7.29 (t, 1H), 7.00 (dd, 1H), 6.94 (d, 1H), 6.35 (d,1H), 4.17 (t, 2H), 3.92 (s, 3H), 2.45 (m, 10H), 2.20 (s, 3H), 1.96 (m,2H).

Melting point: 82-84° C.

Yield: 48%

Example 233-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₁ClF₂N₄O₅S Mw. 633.12

LC/MS purity: 98%, m/z 631 [M−M]⁻, 633 [M+H]⁺ Rt. 3.24 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 7.91 (dd, 1H),7.77 (m, 1H), 7.59 (t, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.25 (t, 1H),7.06 (d, 1H), 6.90 (d, 1H), 6.36 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H),2.46 (bs, 10H), 2.22 (s, 3H), 1.96 (m, 2H).

Melting point: 108-110° C.

Yield: 57%

Example 24N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₁H₃₂F₄N₄O₅S Mw. 648.68

LC/MS purity: 99%, m/z 647 [M−H]⁻, 649 [M+H]⁺ Rt. 3.11 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.44 (d, 1H), 8.14 (d, 1H), 7.95(d, 1H), 7.80 (m, 2H), 7.47 (s, 1H), 7.36 (s, 1H), 7.24 (t, 1H), 7.02(dd, 1H), 6.90 (d, 1H), 6.35 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.45(bs, 10H), 2.23 (s, 3H), 1.96 (m, 2H).

Melting point: 102-106° C.

Yield: 26%

Example 25N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide

C₃₁H₃₂F₄N₄O₆S Mw. 664.68

LC/MS purity: 100%, m/z 663 [M−H]⁻, 665 [M+H]⁺ Rt. 3.26 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.8 (bs, 1H), 8.44 (d, 1H), 8.01 (d, 1H),7.73 (t, 1H), 7.52 (m, 2H), 7.47 (s, 1H), 7.36 (s, 1H), 7.26 (t, 1H),7.07 (d, 1H), 6.91 (d, 1H), 6.33 (d, 1H), 4.18 (t, 2H), 3.91 (s, 3H),2.44 (bs, 10H), 2.23 (s, 3H), 1.96 (m, 2H).

Melting point: 86-90° C.

Yield: 23%

Example 262-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₂F₂N₄O₅S Mw. 598.67

LC/MS purity: 100%, m/z 597 [M−H]⁻, 599 [M+H]⁺ Rt. 2.85 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.5 (bs, 1H), 8.43 (d, 1H), 7.88 (t, 1H),7.68 (d, 1H), 7.47-7.28 (m, 5H), 7.09 (d, 1H), 6.96 (d, 1H), 6.33 (d,1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.43 (bs, 10H), 2.20 (s, 3H), 1.96 (m,2H).

Melting point: 185-186° C.

Yield: 28%

Example 274-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₁ClF₂N₄O₅S Mw. 633.12

LC/MS purity: 100%, m/z 631 [M−H]⁻, 633 [M+H]⁺ Rt. 3.05 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.44 (d, 1H), 7.85 (t, 1H), 7.63(d, 1H), 7.48 (s, 1H), 7.43 (d, 1H), 7.37 (s, 1H), 7.22 (t, 1H), 7.04(d, 1H), 6.89 (d, 1H), 6.35 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.50(bs, 10H), 2.25 (s, 3H), 1.98 (m, 2H).

Melting point: 106-110° C.

Yield: 26%

Example 28N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methyl-benzenesulfonamide

C₃₁H₃₅FN₄O₅S Mw. 594.71

LC/MS purity: 99%, m/z 593 [M−H]⁻, 595 [M+H]⁺ Rt. 3.28 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.43 (d, 1H), 7.91 (t, 1H),7.53-7.24 (m, 6H), 7.05 (d, 1H), 6.94 (d, 1H), 6.32 (d, 1H), 4.17 (t,2H), 3.91 (s, 3H), 2.62 (s, 3H), 2.40 (m, 10H), 2.16 (s, 3H), 1.95 (m,2H).

Melting point: 73-75° C.

Yield: 35%

Example 292-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₂ClFN₄O₅S Mw. 615.13

LC/MS purity: 99%, m/z 613 [M−H]⁻, 615 [M+H]⁺ Rt. 3.09 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1H), 8.43 (d, 1H), 8.08 (d, 1H),7.62 (m, 2H), 7.52 (m, 1H), 7.46 (s, 1H), 7.36 (s, 1H), 7.26 (t, 1H),7.06 (dd, 1H), 6.94 (d, 1H), 6.32 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H),2.43 (m, 10H), 2.19 (s, 3H), 1.96 (m, 2H).

Melting point: 96-98° C.

Yield: 36%

Example 303-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₃F₃N₄O₆S Mw. 646.69

LC/MS purity: 100%, m/z 645 [M−H]⁻, 647 [M+H]⁺ Rt. 3.15 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 7.65-7.26 (m, 8H), 7.09 (d,1H), 6.95 (d, 1H), 6.33 (d, 1H), 4.17 (t, 2H), 3.92 (s, 3H), 3.51 (m,1H), 2.43 (m, 10H), 2.20 (s, 3H), 1.96 (m, 2H).

Melting point: 95-97° C.

Yield: 41%

Example 31

Thiophene-2-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₁FN₄O₅S₂ Mw. 586.71

LC/MS purity: 99%, m/z 585 [M−H]⁻, 587 [M+H]⁺ Rt. 2.81 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.1 (bs, 1H), 8.45 (d, 1H), 7.88 (d, 1H),7.56 (d, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.32 (t, 1H), 7.13 (m, 2H),7.00 (d, 1H), 6.36 (d, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 2.43 (m, 10H),2.21 (s, 3H), 1.96 (m, 2H).

Melting point: 201-202° C.

Yield: 46%

Example 322,6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₁Cl₂FN₄O₅S Mw. 649.57

LC/MS purity: 99%, m/z 647 [M−H]⁻, 649 [M+H]⁺ Rt. 3.03 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.43 (d, 1H), 7.59 (m, 2H),7.48 (m, 2H), 7.36 (s, 1H), 7.25 (t, 1H), 7.05 (d, 1H), 6.90 (d, 1H),6.33 (d, 1H), 4.18 (t, 2H), 3.91 (s, 3H), 2.50 (bs, 10H), 2.20 (s, 3H),1.97 (m, 2H).

Melting point: 113-116° C.

Yield: 38%

Example 33N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide

C₃₁H₃₅FN₄O₆S Mw. 610.71

LC/MS purity: 97%, m/z 609 [M−H]⁻, 611 [M+H]⁺ Rt. 3.33 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.42 (d, 1H), 7.82 (d, 1H),7.62 (t, 1H), 7.45 (s, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 7.21 (d, 1H),7.14-6.99 (m, 3H), 6.28 (d, 1H), 4.17 (t, 2H), 3.90 (s, 6H), 2.39 (m,10H), 2.15 (s, 3H), 1.94 (m, 2H).

Melting point: 168-170° C.

Yield: 36%

Example 343,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide

C₃₁H₃₂Cl₂FN₃O₆S Mw. 664.59

LC/MS purity: 97%, m/z 662 [M−H]⁻, 664 [M+H]⁺ Rt. 3.91 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 7.88 (bs, 1H),7.76 (bs, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.20 (t, 1H), 7.02 (d, 1H),6.87 (d, 1H), 6.36 (d, 1H), 4.19 (t, 2H), 3.92 (s, 6H), 2.61 (bs, 6H),2.03 (bs, 2H), 1.90 (bs, 4H), 1.80 (bs, 2H).

Melting point: 173-175° C.

Yield: 27%

Example 353,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide

C₃₁H₃₃Cl₂FN₄O₆S Mw. 679.60

LC/MS purity: 98%, m/z 677 [M−H]⁻, 679 [M+H]⁺ Rt. 3.79 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.44 (d, 1H), 7.93 (d, 1H),7.76 (d, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.25 (t, 1H), 7.05 (dd, 1H),6.91 (d, 1H), 6.36 (d, 1H), 4.18 (t, 2H), 3.92 (s, 6H), 2.50 (bs, 10H),2.25 (s, 3H), 1.97 (m, 2H).

Melting point: 183-185° C.

Yield: 36%

Example 36N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₄FN₃O₅S Mw. 579.70

LC/MS purity: 99%, m/z 578 [M−H]⁻, 580 [M+H]⁺ Rt. 3.70 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.44 (d, 1H), 7.80 (d, 2H),7.58 (m, 3H), 7.47 (s, 1H), 7.37 (s, 1H), 7.28 (t, 1H), 7.09 (d, 1H),6.95 (d, 1H), 6.33 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.80 (m, 2H),2.45 (m, 2H), 1.96 (m, 2H), 1.90 (m, 1H), 1.58 (m, 4H), 1.38 (m, 1H),0.86 (m, 1H), 0.84 (d, 3H)

Melting point: 160-161° C.

Yield: 32%

Example 373-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₃F₂N₃O₅S Mw. 597.69

LC/MS purity: 99%, m/z 596 [M−H]⁻, 598 [M+H]⁺ Rt. 3.55 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.44 (d, 1H), 7.62 (bs, 2H),7.57 (t, 1H), 7.45 (m, 2H), 7.37 (s, 1H), 7.25 (t, 1H), 7.07 (dd, 1H),6.92 (d, 1H), 6.35 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.86 (m, 2H),2.53 (m, 2H), 1.98 (m, 3H), 1.65 (m, 4H), 1.50 (m, 1H), 0.88 (m, 1H),0.84 (d, 3H)

Melting point: 113-115° C.

Yield: 26%

Example 382-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₃ClFN₃O₅S Mw. 614.14

LC/MS purity: 98%, m/z 612[M−H]⁻, 614 [M+H]⁺ Rt. 3.67 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.43 (d, 1H), 8.08 (d, 1H),7.62 (bs, 2H), 7.52 (m, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 7.26 (t, 1H),7.06 (d, 1H), 6.97 (d, 1H), 6.33 (d, 1H), 4.18 (t, 2H), 3.91 (s, 3H),2.87 (m, 2H), 2.55 (m, 2H), 1.98 (m, 3H), 1.69 (m, 4H), 1.49 (m, 1H),0.89 (m, 1H), 0.84 (d, 3H)

Melting point: 115-118° C.

Yield: 22%

Example 39

′N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-trifluoromethyl-benzenesulfonamide

C₃₂H₃₃F₄N₃O₅S Mw. 647.69

LC/MS purity: 99%, m/z 646[M−H]⁻, 648 [M+H]⁺ Rt. 3.01 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.43 (d, 1H), 8.02 (m, 3H), 7.80(t, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.25 (t, 1H), 7.07 (dd, 1H), 6.91(d, 1H), 6.32 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 2.96 (m, 2H), 2.63(m, 2H), 2.55 (m, 3H), 1.82 (m, 1H), 1.66 (m, 3H), 1.52 (m, 1H), 0.92(m, 1H), 0.84 (d, 3H)

Melting point: 128-130° C.

Yield: 41%

Example 40N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-nitro-benzenesulfonamide

C₃₁H₃₃FN₄O₇S Mw. 624.69

LC/MS purity: 100%, m/z 623 [M−H]⁻, 625 [M+H]⁺ Rt. 3.26 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.43 (d, 1H), 7.94 (m, 1H),7.73 (m, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 7.10 (t, 1H), 6.89 (dd, 1H),6.76 (d, 1H), 6.36 (d, 1H), 4.21 (t, 2H), 3.93 (s, 3H), 3.09 (m, 2H),2.80 (m, 2H), 2.22 (m, 1H), 2.09 (m, 3H), 1.68 (m, 3H), 1.56 (m, 1H),0.96 (m, 1H), 0.87 (d, 3H)

Melting point: 136-138° C.

Yield: 19%

Example 413-Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₂H₃₃FN₄O₅S Mw. 604.71

LC/MS purity: 99%, m/z 603 [M−H]⁻, 605 [M+H]⁺ Rt. 3.29 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 8.14 (s, 1H),8.05 (t, 2H), 7.75 (t, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.22 (t, 1H),7.04 (dd, 1H), 6.32 (d, 1H), 6.35 (d, 1H), 4.20 (t, 2H), 3.92 (s, 3H),2.96 (m, 2H), 2.64 (m, 2H), 2.05 (m, 3H), 1.85 (m, 1H), 1.66 (m, 3H),1.56 (m, 1H), 0.92 (m, 1H), 0.86 (d, 3H)

Melting point: 125-127° C.

Yield: 26%

Example 42N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-methoxy-benzenesulfonamide

C₃₂H₃₆FN₃O₆S Mw. 609.72

LC/MS purity: 98%, m/z 608 [M−H]⁻, 610 [M+H]⁺ Rt. 3.75 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.44 (d, 1H), 7.49 (m, 2H),7.36 (m, 2H), 7.30 (m, 2H), 7.20 (d, 1H), 7.14 (d, 1H), 6.99 (d, 1H),6.35 (d, 1H), 4.18 (t, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 2.82 (m, 2H),2.48 (m, 2H), 1.97 (m, 2H), 1.90 (m, 1H), 1.62 (m, 4H), 1.49 (m, 1H),0.92 (m, 1H), 0.84 (d, 3H)

Melting point: 172-174° C.

Yield: 35%

Example 433-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₂H₃₄F₃N₃O₆S Mw. 645.70

LC/MS purity: 99%, m/z 644 [M−H]⁻, 646 [M+H]⁺ Rt. 3.70 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (bs, 1H), 7.65-7.32 (m,7H), 7.09 (d, 1H), 6.96 (d, 1H), 6.34 (bs, 1H), 4.18 (bs, 2H), 3.92 (s,3H), 3.57 (m, 1H), 2.89 (bs, 2H), 2.55 (bs, 2H), 2.00 (bs, 3H), 1.63(bs, 4H), 1.51 (m, 1H), 0.88 (m, 1H), 0.86 (d, 3H)

Melting point: 99-100° C.

Yield: 25%

Example 44N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methyl-benzenesulfonamide

C₃₂H₃₆FN₃O₅S Mw. 593.72

LC/MS purity: 99%, m/z 592 [M−H]⁻, 594 [M+H]⁺ Rt. 3.89 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.7 (bs, 1H), 8.43 (d, 1H), 7.92 (d, 1H),7.51-7.25 (m, 6H), 7.05 (d, 1H), 6.94 (d, 1H), 6.32 (d, 1H), 4.17 (t,2H), 3.91 (s, 3H), 2.80 (m, 2H), 2.62 (s, 3H), 2.52 (m, 2H), 1.96 (m,2H), 1.88 (m, 1H), 1.61 (m, 4H), 1.48 (m, 1H), 0.90 (m, 1H), 0.84 (d,3H)

Melting point: 99-100° C.

Yield: 26%

Example 45N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide

C₃₂H₃₃F₄N₃O₆S Mw. 663.69

LC/MS purity: %, m/z 642 [M−H]⁻, 644 [M+H]⁺ Rt. 3.84 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.43 (d, 1H), 7.98 (d, 1H),7.67 (t, 1H), 7.48 (bs, 3H), 7.37 (s, 1H), 7.18 (t, 1H), 7.00 (d, 1H),6.84 (d, 1H), 6.33 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.83 (m, 2H),2.56 (m, 2H), 1.99 (m, 3H), 1.63 (m, 4H), 1.51 (m, 1H), 0.89 (m, 1H),0.84 (d, 3H)

Melting point: 128-130° C.

Yield: 21%

Example 46N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-trifluoromethoxy-benzenesulfonamide

C₃₂H₃₃F₄N₃O₆S Mw. 663.69

LC/MS purity: 99%, m/z 662 [M−H]⁻, 664 [M+H]⁺ Rt. 3.87 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.42 (d, 1H), 7.79 (d, 1H), 7.66(m, 2H), 7.56 (d, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.19 (t, 1H), 7.01(dd, 1H), 6.86 (d, 1H), 6.32 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.87(m, 2H), 2.54 (m, 2H), 1.98 (m, 3H), 1.65 (m, 4H), 1.51 (m, 1H), 0.88(m, 1H), 0.84 (d, 3H)

Melting point: 102-104° C.

Yield: 21%

Example 472,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂F₃N₃O₅S Mw. 615.68

LC/MS purity: 99%, m/z 614 [M−H]⁻, 616 [M+H]⁺ Rt. 3.48 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 7.92 (m, 1H),7.48 (s, 2H), 7.44 (d, 1H), 7.38 (s, 1H), 7.25 (m, 2H), 7.05 (dd, 1H),6.91 (d, 1H), 6.35 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 2.92 (m, 2H),2.60 (m, 2H), 2.03 (m, 3H), 1.78 (m, 1H), 1.65 (m, 3H), 1.54 (m, 1H),0.92 (m, 1H), 0.85 (d, 3H)

Melting point: 118-120° C.

Yield: 18%

Example 483,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂F₃N₃O₅S Mw. 615.68

LC/MS purity: 99%, m/z 614 [M−H]⁻, 616 [M+H]⁺ Rt. 3.59 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.43 (d, 1H), 7.78 (t, 1H),7.59 (m, 2H), 7.48 (s, 1H), 7.37 (s, 1H), 7.21 (t, 2H), 7.04 (d, 1H),6.88 (d, 1H), 6.36 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.98 (m, 2H),2.55 (m, 2H), 2.00 (m, 3H), 1.70 (m, 3H), 1.51 (m, 1H), 0.90 (m, 1H),0.84 (d, 3H)

Melting point: 120-122° C.

Yield: 34%

Example 492,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₁F₄N₃O₅S Mw. 633.67

LC/MS purity: 100%, m/z 632 [M−H]⁻, 634 [M+H]⁺ Rt. 3.46 min. (Method B)

LC/MS purity: 100%, m/z 632 [M−H]⁻, 634 [M+H]⁺ Rt. 3.46 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 7.64 (m, 1H),7.50 (s, 1H), 7.39 (m, 2H), 7.16 (t, 1H), 6.98 (dd, 1H), 6.84 (d, 1H),6.37 (d, 1H), 4.21 (t, 2H), 3.93 (s, 3H), 3.11 (m, 2H), 2.81 (m, 2H),2.16 (m, 4H), 1.69 (m, 3H), 1.58 (m, 1H), 0.96 (m, 1H), 0.88 (d, 3H)

Melting point: 134-136° C.

Yield: 28%

Example 502,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂Cl₂FN₃O₅S Mw. 648.59

LC/MS purity: 99%, m/z 646 [M−H]⁻, 648 [M+H]⁺ Rt. 3.03 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.44 (d, 1H), 7.98 (s, 1H),7.60 (bs, 2H), 7.48 (s, 1H), 7.39 (s, 1H), 7.18 (t, 1H), 6.98 (d, 1H),6.86 (d, 1H), 6.35 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 3.04 (m, 2H),2.74 (m, 2H), 2.23 (m, 1H), 2.07 (m, 2H), 1.95 (m, 1H), 1.68 (m, 3H),1.56 (m, 1H), 0.95 (m, 1H), 0.87 (d, 3H)

Melting point: 127-129° C.

Yield: 29%

Example 512,6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂Cl₂FN₃O₅S Mw. 648.59

LC/MS purity: 99%, m/z 646 [M−H]⁻, 648 [M+H]⁺ Rt. 3.59 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.43 (d, 1H), 7.58 (d, 1H),7.57 (s, 1H), 7.48 (m, 2H), 7.38 (s, 1H), 7.22 (t, 1H), 7.02 (dd, 1H),6.88 (d, 1H), 6.34 (d, 1H), 4.20 (t, 2H), 3.92 (s, 3H), 3.01 (m, 2H),2.70 (m, 2H), 2.16 (m, 1H), 2.05 (m, 2H), 1.91 (m, 1H), 1.68 (m, 3H),1.55 (m, 1H), 0.98 (m, 1H), 0.86 (d, 3H)

Melting point: 119-121° C.

Yield: 16%

Example 523,4-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂Cl₂FN₃O₅S Mw. 648.59

LC/MS purity: 99%, m/z 646 [M−H]⁻, 648 [M+H]⁺ Rt. 3.11 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.44 (d, 1H), 7.92 (d, 1H),7.80 (d, 1H), 7.71 (dd, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.23 (t, 1H),7.05 (dd, 1H), 6.89 (d, 1H), 6.36 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H),2.98 (m, 2H), 2.67 (m, 2H), 2.13 (m, 1H), 2.03 (m, 2H), 1.86 (m, 1H),1.67 (m, 3H), 1.57 (m, 1H), 0.92 (m, 1H), 0.86 (d, 3H)

Melting point: 123-124° C.

Yield: 15%

Example 533,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂Cl₂FN₃O₅S Mw. 648.59

LC/MS purity: 98%, m/z 646 [M−H]⁻, 648 [M+H]⁺ Rt. 3.13 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.44 (d, 1H), 7.81 (d, 1H),7.69 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 7.20 (t, 1H),7.01 (dd, 1H), 6.86 (d, 1H), 6.36 (d, 1H), 4.21 (t, 2H), 3.93 (s, 3H),3.06 (m, 2H), 2.76 (m, 2H), 2.23 (m, 1H), 2.06 (m, 2H), 1.97 (m, 1H),1.69 (m, 3H), 1.57 (m, 1H), 0.92 (m, 1H), 0.87 (d, 3H)

Melting point: 126-128° C.

Yield: 19%

Example 543-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂ClF₂N₃O₅S Mw. 632.13

LC/MS purity: 98%, m/z 630 [M−H]⁻, 632 [M+H]⁺ Rt. 3.50 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.43 (d, 1H), 7.81 (d, 1H),7.76 (d, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.33 (t, 1H), 7.19 (t, 1H),7.02 (dd, 1H), 6.87 (d, 1H), 6.36 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H),3.03 (m, 2H), 2.73 (m, 2H), 2.20 (m, 1H), 2.06 (m, 2H), 1.94 (m, 1H),1.68 (m, 3H), 1.56 (m, 1H), 0.93 (m, 1H), 0.86 (d, 3H)

Melting point: 125-127° C.

Yield: 18%

Example 552-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-5-methyl-benzenesulfonamide

C₃₂H₃₅F₂N₃O₅S Mw. 611.71

LC/MS purity: 99%, m/z 610 [M−H]⁻, 612 [M+H]⁺ Rt. 3.73 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 7.69 (d, 1H),7.49 (d, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.30 (td, 2H), 7.12 (dd, 1H),6.99 (d, 1H), 6.34 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 2.90 (m, 2H),2.57 (s, 2H), 2.34 (s, 3H), 2.01 (m, 3H), 1.74 (m, 1H), 1.61 (m, 3H),1.52 (m, 1H), 0.90 (m, 1H), 0.85 (d, 3H)

Melting point: 149-151° C.

Yield: 23%

Example 563-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-4-methyl-benzenesulfonamide

C₃₂H₃₅F₂N₃O₅S Mw. 611.71

LC/MS purity: 99%, m/z 610 [M−H]⁻, 612 [M+H]⁺ Rt. 3.85 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 7.52 (m, 4H),7.38 (s, 1H), 7.31 (t, 1H), 7.13 (dd, 1H), 6.98 (d, 1H), 6.36 (d, 1H),4.19 (t, 2H), 3.92 (s, 3H), 2.88 (m, 2H), 2.54 (m, 2H), 2.29 (m, 3H),1.99 (m, 3H), 1.63 (m, 4H), 1.54 (m, 1H), 0.89 (m, 1H), 0.84 (d, 3H)

Melting point: 174-176° C.

Yield: 19%

Example 573-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂ClF₂N₃O₅S Mw. 632.13

LC/MS purity: 96%, m/z 630 [M−H]⁻, 632 [M+H]⁺ Rt. 2.97 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.44 (d, 1H), 7.91 (dd, 1H),7.77 (m, 1H), 7.58 (t, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.24 (t, 1H),7.06 (dd, 1H), 6.89 (d, 1H), 6.36 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H),2.83 (m, 2H), 2.61 (s, 2H), 2.03 (m, 3H), 1.78 (m, 1H), 1.63 (m, 3H),1.52 (m, 1H), 0.91 (m, 1H), 0.85 (d, 3H)

Melting point: 124-126° C.

Yield: 30%

Example 58 Naphthalene-1-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₅H₃₆FN₃O₅S Mw. 629.76

LC/MS purity: 99%, m/z 628 [M−H]⁻, 630 [M+H]⁺ Rt. 2.95 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.82 (d, 1H), 8.39 (d, 1H),8.20 (m, 2H), 8.06 (d, 1H), 7.65 (m, 3H), 7.42 (s, 1H), 7.35 (s, 1H),7.16 (t, 1H), 6.99 (d, 1H), 6.85 (d, 1H), 6.26 (d, 1H), 4.16 (t, 2H),3.89 (s, 3H), 2.83 (m, 2H), 2.48 (m, 2H), 1.96 (m, 3H), 1.62 (m, 4H),1.49 (m, 1H), 0.89 (m, 1H), 0.84 (d, 3H)

Melting point: 131-133° C.

Yield: 21%

Example 59N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-phenoxy-benzenesulfonamide

C₃₇H₃₈FN₃O₆S Mw. 671.79

LC/MS purity: 98%, m/z 670 [M−H]⁻, 672 [M+H]⁺ Rt. 3.18 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.44 (d, 1H), 7.62-7.22 (m,10H), 7.04 (m, 3H), 6.93 (d, 1H), 6.35 (d, 1H), 4.19 (t, 2H), 3.93 (s,3H), 2.86 (m, 2H), 2.48 (m, 2H), 1.99 (m, 3H), 1.65 (m, 4H), 1.51 (m,1H), 0.88 (m, 1H), 0.84 (d, 3H)

Melting point: 146-147° C.

Yield: 24%

Example 60 Cyclopropanesulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₄FN₃O₅S Mw. 543.66

LC/MS purity: 96%, m/z 542[M−H]⁻, 544 [M+H]⁺ Rt. 3.65 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.47 (d, 1H), 7.52 (s, 1H),7.45 (d, 1H), 7.39 (s, 1H), 7.28 (d, 1H), 7.17 (d, 1H), 6.45 (d, 1H),4.19 (t, 2H), 3.94 (s, 3H), 3.17 (m, 1H), 2.77 (m, 3H), 2.44 (m, 2H),1.96 (m, 2H), 1.84 (m, 1H), 1.61 (m, 3H), 1.48 (m, 1H), 0.99 (m, 2H),0.97 (m, 2H), 0.88 (m, 1H), 0.84 (d, 3H)

Melting point: 158-160° C.

Yield: 11%

Example 61 1-Methyl-1H-pyrazole-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₄FN₅O₅S Mw. 583.69

LC/MS purity: 97%, m/z 582 [M−H]⁻, 584 [M+H]⁺ Rt. 3.09 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.45 (d, 1H), 7.84 (d, 1H),7.49 (s, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.15 (dd, 1H), 7.00 (d, 1H),6.63 (d, 1H), 6.38 (d, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 3.90 (s, 3H),2.78 (m, 2H), 2.44 (m, 2H), 1.96 (m, 2H), 1.85 (m, 1H), 1.58 (m, 4H),1.46 (m, 1H), 0.85 (m, 1H), 0.83 (d, 3H)

Melting point: 164-166° C.

Yield: 31%

Example 62 5-Methyl-thiophene-2-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₀H₃₄FN₃O₅S₂ Mw. 599.75

LC/MS purity: 99%, m/z 598 [M−H]⁻, 600 [M+H]⁺ Rt. 3.62 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.45 (d, 1H), 7.49 (s, 1H),7.38 (s, 1H), 7.36 (s, 1H), 7.30 (t, 1H), 7.12 (dd, 1H), 6.98 (d, 1H),6.83 (d, 1H), 6.38 (d, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 2.85 (m, 2H),2.54 (m, 2H), 2.46 (s, 3H), 1.97 (m, 3H), 1.63 (m, 4H), 1.50 (m, 1H),0.88 (m, 1H), 0.84 (d, 3H)

Melting point: 99-101° C.

Yield: 29%

Example 63 5-Chloro-thiophene-2-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₁ClFN₃O₅S₂Mw. 620.17

LC/MS purity: 99%, m/z 618 [M−H]⁻, 620 [M+H]⁺ Rt. 3.50 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.46 (d, 1H), 7.51 (s, 1H),7.40 (s, 1H), 7.33 (s, 1H), 7.23 (t, 1H), 7.12 (d, 1H), 7.04 (d, 1H),6.91 (d, 1H), 6.39 (d, 1H), 4.21 (t, 2H), 3.93 (s, 3H), 3.16 (m, 2H),2.79 (m, 2H), 2.28 (s, 1H), 2.09 (m, 3H), 1.68 (m, 3H), 1.58 (m, 1H),0.96 (m, 1H), 0.88 (d, 3H)

Melting point: 100-103° C.

Yield: 19%

Example 64 2,4-Dichloro-thiophene-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₀Cl₂FN₃O₅S₂ Mw. 654.61

LC/MS purity: 98%, m/z 652 [M−H]⁻, 654 [M+H]⁺ Rt. 3.03 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.45 (d, 1H), 7.51 (s, 1H),7.38 (s, 1H), 7.18 (s, 1H), 7.16 (t, 1H), 6.97 (d, 1H), 6.82 (d, 1H),6.39 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H), 3.17 (m, 2H), 2.68 (m, 2H),2.18 (m, 1H), 2.06 (m, 2H), 1.88 (m, 1H), 1.67 (m, 3H), 1.53 (m, 1H),0.93 (m, 1H), 0.86 (d, 3H)

Melting point: 119-121° C.

Yield: 39%

Example 65

Thiophene-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₂FN₃O₅S₂ Mw. 585.72

LC/MS purity: 99%, m/z 584 [M−H]⁻, 586 [M+H]⁺ Rt. 3.49 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.44 (d, 1H), 8.19 (d, 1H),7.71 (m, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.30 (m, 2H), 7.13 (dd, 1H),6.99 (d, 1H), 6.36 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.80 (m, 2H),2.46 (m, 2H), 1.95 (m, 2H), 1.87 (m, 1H), 1.66 (m, 1H), 1.60 (m, 3H),1.48 (m, 1H), 0.92 (m, 1H), 0.84 (d, 3H)

Melting point: 174-176° C.

Yield: 28%

Example 663-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylicacid methyl ester

C₃₁H₃₄FN₃O₇S₂ Mw. 643.76

LC/MS purity: 98%, m/z 642 [M−H]⁻, 644 [M+H]⁺ Rt. 3.78 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.45 (d, 1H), 7.94 (d, 1H),7.48 (s, 1H), 7.47 (s, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.13 (dd, 1H),6.98 (d, 1H), 6.36 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 3.88 (m, 3H),2.85 (m, 2H), 2.54 (s, 2H), 1.96 (m, 3H), 1.65 (m, 4H), 1.47 (m, 1H),0.92 (d, 1H), 0.92 (d, 3H)

Melting point: 132-134° C.

Yield: 9%

Example 67 Benzo[b]thiophene-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₃H₃₄FN₃O₅S₂ Mw. 635.78

LC/MS purity: 99%, m/z 634 [M−H]⁻, 636 [M+H]⁺ Rt. 3.86 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.57 (s, 1H), 8.41 (d, 1H),8.25 (d, 1H), 8.09 (d, 1H), 7.54 (m, 2H), 7.45 (s, 1H), 7.36 (s, 1H),7.22 (t, 1H), 7.09 (d, 1H), 6.93 (d, 1H), 6.29 (d, 1H), 4.16 (t, 2H),3.90 (s, 3H), 2.85 (m, 2H), 2.51 (m, 2H), 1.96 (m, 3H), 1.65 (m, 4H),1.49 (m, 1H), 0.92 (m, 1H), 0.84 (d, 3H)

Melting point: 126-128° C.

Yield: 26%

Example 68 1-Ethyl-1H-pyrazole-4-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₀H₃₆FN₅O₅S Mw. 597.71

LC/MS purity: 99%, m/z 596 [M−H], 598 [M+H]⁺ Rt. 3.35 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.45 (d, 1H), 8.33 (s, 1H),7.75 (s, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.36 (t, 1H), 7.16 (d, 1H),7.03 (d, 1H), 6.38 (d, 1H), 4.16 (m, 4H), 3.93 (s, 3H), 2.80 (m, 2H),2.45 (m, 2H), 1.96 (m, 2H), 1.85 (m, 1H), 1.65 (m, 1H), 1.59 (m, 3H),1.48 (m, 1H), 1.34 (t, 3H), 0.91 (m, 1H), 0.83 (d, 3H)

Melting point: 152-154° C.

Yield: 43%

Example 693-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₃ClFN₃O₅S Mw. 614.14

LC/MS purity: 98%, m/z 612 [M−H]⁻, 614 [M+H]⁺ Rt. 2.90 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 7.75 (s, 1H),7.74 (d, 1H), 7.67 (d, 1H), 7.58 (t, 1H), 7.48 (s, 1H), 7.38 (s, 1H),7.25 (t, 1H), 7.06 (d, 1H), 6.91 (d, 1H), 6.35 (d, 1H), 4.19 (t, 2H),3.92 (s, 3H), 2.89 (m, 2H), 2.55 (m, 2H), 1.99 (m, 3H), 1.69 (m, 4H),1.51 (m, 1H), 0.92 (m, 1H), 0.85 (d, 3H)

Melting point: 110-112° C.

Yield: 43%

Example 70N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-methyl-benzenesulfonamide

C₃₂H₃₆FN₃O₅S Mw. 593.72

LC/MS purity: 98%, m/z 592 [M−H]⁻, 594 [M+H]⁺ Rt. 2.85 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 7.63 (s, 1H),7.60 (d, 1H), 7.47 (m, 3H), 7.38 (s, 1H), 7.31 (s, 1H), 7.12 (d, 1H),6.95 (d, 1H), 6.34 (d, 1H), 4.18 (t, 2H), 3.91 (s, 3H), 2.80 (m, 2H),2.46 (m, 2H), 2.37 (s, 3H), 1.96 (m, 2H), 1.85 (m, 1H), 1.60 (m, 4H),1.46 (m, 1H), 0.93 (m, 1H), 0.84 (d, 3H)

Melting point: 168-170° C.

Yield: 37%

Example 71N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide

C₃₂H₃₆FN₃O₆S Mw. 609.72

LC/MS purity: 100%, m/z 608 [M−H]⁻, 610 [M+H]⁺ Rt. 2.71 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.43 (d, 1H), 7.83 (d, 1H),7.61 (t, 1H), 7.45 (s, 1H), 7.36 (s, 1H), 7.29 (t, 1H), 7.20 (d, 1H),7.08 (m, 2H), 6.98 (d, 1H), 6.29 (d, 1H), 4.17 (t, 2H), 3.89 (s, 6H),2.77 (m, 2H), 2.42 (m, 2H), 1.95 (m, 2H), 1.82 (m, 1H), 1.61 (m, 4H),1.51 (m, 1H), 0.93 (m, 1H), 0.83 (d, 3H)

Melting point: 175-176° C.

Yield: 35%

Example 723-Cyano-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₂H₃₂F₂N₄O₅S Mw. 622.70

LC/MS purity: 99%, m/z 621 [M−H]⁻¹, 623 [M+H]⁺ Rt. 2.82 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 8.22 (d, 1H),8.11 (m, 1H), 7.64 (t, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.16 (t, 1H),6.99 (d, 1H), 6.84 (d, 1H), 6.37 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H),2.99 (m, 2H), 2.67 (m, 2H), 2.14 (m, 1H), 2.06 (m, 2H), 1.87 (m, 1H),1.67 (m, 3H), 1.54 (m, 1H), 0.93 (m, 1H), 0.83 (d, 3H)

Melting point: 125-127° C.

Yield: 8%

Example 73 2-Phenyl-ethenesulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₃H₃₆FN₃O₅S Mw. 605.73

LC/MS purity: 98%, m/z 604 [M−H]⁻, 606 [M+H]⁺ Rt. 2.91 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.41 (d, 1H), 7.70 (bs, 2H),7.48 (s, 1H), 7.42-7.24 (m, 7H), 7.17 (d, 1H), 7.03 (d, 1H), 6.37 (d,1H), 4.17 (bs, 2H), 3.93 (s, 3H), 2.77 (m, 2H), 2.43 (m, 2H), 1.96 (m,2H), 1.84 (m, 1H), 1.59 (m, 4H), 1.48 (m, 1H), 0.92 (m, 1H), 0.83 (d,3H)

Melting point: 104-106° C.

Yield: 27%

Example 74 Quinoline-8-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₄H₃₅FN₄O₅S Mw. 630.74

LC/MS purity: 98%, m/z 629 [M−H]⁻, 631 [M+H]⁺ Rt. 2.62 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 9.15 (d, 1H), 8.55 (d, 1H),8.45 (d, 1H), 8.39 (d, 1H), 8.33 (d, 1H), 7.74 (m, 2H), 7.40 (s, 1H),7.34 (s, 1H), 7.17 (t, 1H), 7.14 (d, 1H), 6.97 (d, 1H), 6.21 (d, 1H),4.15 (t, 2H), 3.87 (s, 3H), 2.78 (m, 2H), 2.43 (m, 2H), 1.94 (m, 2H),1.82 (m, 1H), 1.58 (m, 5H), 0.89 (m, 1H), 0.82 (d, 3H)

Melting point: 190-191° C.

Yield: 25%

Example 753,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide

C₃₂H₃₄Cl₂FN₃O₆S Mw. 678.61

LC/MS purity: 97%, m/z 676 [M−H]⁻, 678 [M+H]⁺ Rt. 3.19 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 7.90 (d, 1H),7.76 (d, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.22 (t, 1H), 7.04 (dd, 1H),6.89 (d, 1H), 6.36 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 3.91 (s, 3H),2.96 (m, 2H), 2.64 (m, 2H), 2.03 (m, 3H), 1.82 (m, 1H), 1.66 (m, 3H),1.51 (m, 1H), 0.92 (m, 1H), 0.86 (d, 3H)

Melting point: 145-146° C.

Yield: 17%

Example 763,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide

C₃₀H₃₀Cl₂FN₃O₇S Mw. 666.56

LC/MS purity: 98%, m/z 664 [M−H]⁻, 666 [M+H]⁺ Rt. 3.00 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.44 (d, 1H), 8.00 (d, 1H),7.79 (d, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.32 (t, 1H), 7.12 (dd, 1H),6.98 (d, 1H), 6.36 (d, 1H), 4.19 (t, 2H), 3.94 (s, 3H), 3.92 (s, 3H),3.59 (m, 4H), 2.49 (m, 2H), 2.42 (m, 4H), 1.97 (m, 2H)

Melting point: 189-191° C.

Yield: 24

Example 772,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₂₉H₂₈F₃N₃O₆S Mw. 603.62

LC/MS purity: 98%, m/z 602 [M−H]⁻, 604 [M+H]⁺ Rt. 2.95 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.44 (d, 1H), 7.68 (m, 1H), 7.48(s, 1H), 7.38 (s, 1H), 7.36-7.24 (m, 3H), 7.14 (dd, 1H), 7.00 (d, 1H),6.34 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 3.59 (m, 4H), 2.49 (m, 2H),2.41 (m, 4H), 1.96 (m, 2H)

Melting point: 190-192° C.

Yield: 23%

Example 78N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethoxy-benzenesulfonamide

C₃₁H₃₁F₄N₃O₆S Mw. 649.67

LC/MS purity: 98%, m/z 648 [M−H]⁻, 650 [M+H]⁺ Rt. 2.90 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 8.00 (d, 1H),7.70 (t, 1H), 7.52 (m, 2H), 7.48 (s, 1H), 7.38 (s, 1H), 7.22 (t, 1H),7.05 (dd, 1H), 6.89 (d, 1H), 6.33 (d, 1H), 4.19 (t, 2H), 3.93 (s, 3H),2.62 (m, 2H), 2.56 (m, 4H), 2.03 (m, 2H), 1.55 (m, 4H), 1.43 (m, 2H)

Melting point: 156-158° C.

Yield: 26%

Example 79

Butane-1-sulfonic acid{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide

C₂₇H₃₄FN₃O₆S Mw. 547.65

LC/MS purity: 98%, m/z 546 [M−H]⁻, 548 [M+H]⁺ Rt. 3.59 min.

¹H NMR (300 MHz, DMSO-d6): 10.14 (s, 1H), 8.47 (d, 1H), 7.51 (s, 1H),7.44 (t, 1H), 7.40 (s, 1H), 7.27 (dd, 1H), 7.14 (d, 1H), 6.46 (d, 1H),4.20 (t, 2H), 3.94 (s, 3H), 3.59 (m, 4H), 3.20 (m, 2H), 2.47 (m, 2H),2.39 (m, 4H), 1.98 (m, 2H), 1.68 (m, 2H), 1.39 (m, 2H), 0.87 (t, 3H)

Melting point: 98-100° C.

Yield: 18%

Example 802,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(piperidin-3-ylmethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₂₈H₂₆F₃N₃O₅S Mw. 573.60

LC/MS purity: %, m/z [M−H]⁻, [M+H]⁺ Rt. min. (Method B)

Yield: 34%

Example 812-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₂₈H₂₇F₂N₃O₆S Mw. 571.60

LC/MS purity: 98%, m/z 570 [M−H]⁻, 572 [M+H]⁺, Rt. 3.06 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.44 (s, 1H), 7.90 (s, 1H), 7.73(s, 1H), 7.38 (m, 5H), 7.15 (d, 1H), 7.03 (d, 1H), 6.33 (s, 1H), 4.27(bs, 2H), 3.90 (s, 3H), 3.59 (s, 4H), 2.79 (bs, 2H), 2.52 (s, 4H)

Melting point: 168-169° C.

Yield: 67%

Example 822,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₂₈H₂₆F₃N₃O₆S Mw. 589.60

LC/MS purity: 97%, m/z 588 [M−H]⁻, 590 [M+H]⁺ Rt. 2.88 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.45 (s, 1H), 7.71 (s, 1H), 7.47(s, 1H), 7.42 (s, 1H), 7.36-7.26 (m, 5H), 7.16 (d, 1H), 7.03 (d, 1H),6.35 (s, 1H), 4.27 (bs, 2H), 3.91 (s, 3H), 3.60 (s, 4H), 2.80 (bs, 2H),2.57 (s, 4H)

Melting point: 182-183° C.

Yield: 32%

Example 832,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₃₀H₃₀F₃N₃O₆S Mw. 617.65

LC/MS purity: 97%, m/z 616 [M−H]⁻, 618 [M+H]⁺ Rt. 3.22 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.1 (bs, 1H), 8.44 (d, 1H), 7.67-7.53 (m,3H), 7.47 (s, 1H), 7.38 (s, 1H), 7.30 (t, 1H), 7.12 (d, 1H), 6.98 (d,1H), 6.35 (d, 1H), 4.17 (t, 2H), 3.92 (s, 3H), 3.58 (m, 4H), 2.39 (m,6H), 1.82 (m, 2H), 1.64 (m, 2H)

Melting point: 156-158° C.

Yield: 29%

Example 842,5-Difluoro-N-{3-fluoro-4-[7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₂₉H₂₈F₃N₃O₅S Mw. 587.62

LC/MS purity: %, m/z [M+H]⁺ Rt. min. (Method B)

Yield: 30%

Example 85N-(3-Fluoro-4-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₀H₃₀F₄N₄O₄S Mw. 618.66

LC/MS purity: 97%, m/z 617 [M−H]⁻, 619 [M+H]⁺ Rt. 3.18 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.50 (d, 1H), 8.15 (d, 1H),7.97-7.78 (m, 4H), 7.52 (m, 1H), 7.43 (dd, 1H), 7.27 (t, 1H), 7.05 (d,1H), 6.93 (d, 1H), 6.49 (d, 1H), 4.16 (t, 2H), 2.44 (m, 10H), 2.19 (s,3H), 1.95 (m, 2H)

Melting point: 101-103° C.

Yield: 27%

Example 86N-(3-Fluoro-4-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₁H₃₂F₄N₄O₅S Mw. 648.68

LC/MS purity: 97%, m/z 647 [M−H]⁻, 649 [M+H]⁺ Rt. 3.07 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.43 (d, 1H), 8.13 (d, 1H), 7.95(d, 1H), 7.80 (m, 2H), 7.47 (s, 1H), 7.38 (s, 1H), 7.25 (t, 1H), 7.05(d, 1H), 6.91 (d, 1H), 6.35 (d, 1H), 4.15 (t, 2H), 3.93 (s, 3H), 2.44(m, 10H), 2.17 (s, 3H), 1.96 (m, 2H)

Melting point: 113-115° C.

Yield: 23%

Example 87N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₁H₃₂ClF₃N₄O₅S Mw. 665.14

LC/MS purity: 99%, m/z 663 [M−H]⁻, 665 [M+H]⁺ Rt. 3.17 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.43 (d, 1H), 8.13 (d, 1H), 7.93(d, 1H), 7.80 (m, 2H), 7.47 (s, 1H), 7.37 (s, 1H), 7.22 (m, 2H), 7.04(d, 1H), 6.26 (s, 1H), 4.18 (bs, 2H), 3.91 (s, 3H), 2.48 (s, 10H), 2.24(s, 3H), 1.96 (m, 2H).

Melting point: 103-105° C.

Yield: 26%

Example 88N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide

C₃₀H₃₀Cl₂F₂N₄O₅S Mw. 667.56

LC/MS purity: %, m/z [M−H]⁻, [M+H]⁺ Rt. min. (Method B)

Yield: 20%

Example 89N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₃H₃₆F₃N₃O₅S Mw. 643.73

LC/MS purity: 99%, m/z 642 [M−H]⁻, 644 [M+H]⁺ Rt. 4.03 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.40 (d, 1H), 8.12 (d, 1H),7.89 (d, 1H), 7.85 (m, 2H), 7.50 (s, 1H), 7.36 (s, 1H), 7.09 (s, 1H),7.02 (m, 2H), 6.17 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.87 (m, 2H),2.47 (m, 2H), 2.01 (m, 3H), 1.93 (m, 4H), 1.58 (m, 2H), 1.33 (m, 1H),1.18 (m, 2H), 0.88 (d, 3H)

Melting point: 165-167° C.

Yield: 25%

Example 902,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₂H₃₅F₂N₃O₆S Mw. 627.71

LC/MS purity: %, m/z [M−H]⁻, [M+H]⁺ Rt. min. (Method B)

Yield: 28%

Example 91N-{4-[6,7-Bis-(2-methoxy-ethoxy)-quinolin-4-yloxy]-3-fluoro-phenyl}-2,6-difluoro-benzenesulfonamide

C₂₇H₂₅F₃N₂O₇S Mw. 578.57

LC/MS purity: %, m/z [M−H]⁻, [M+H]⁺ Rt. min. (Method B)

Yield: 19%

Example 92{4-[2-Fluoro-4-(2-fluoro-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-aceticacid ethyl ester

C₂₆H₂₂F₂N₂O₇S Mw. 544.54

LC/MS purity: 97%, m/z 543 [M−H]⁻, 545 μM⁺ Rt. 3.50 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.99 (s, 1H), 8.45 (d, 1H), 7.91 (t, 1H),7.75 (m, 1H), 7.50 (s, 1H), 7.40 (m, 3H), 7.30 (s, 1H), 7.17 (dd, 1H),7.05 (d, 1H), 6.35 (d, 1H), 5.00 (s, 2H), 4.20 (q, 2H), 3.94 (s, 3H),1.28 (t, 3H)

Melting point: 87-89° C.

Yield: 23%

Example 932-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-N,N-dimethyl-acetamide

C₂₇H₂₃F₄N₃O₆S Mw. 593.56

LC/MS purity: 97%, m/z 592 [M−H]⁻, 594 [M+H]⁺ Rt. 3.24 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1H), 8.43 (d, 1H), 8.15 (d, 1H),8.01 (d, 1H), 7.88 (m, 2H), 7.47 (s, 1H), 7.36 (t, 1H), 7.29 (s, 1H),7.14 (d, 1H), 7.02 (d, 1H), 6.36 (d, 1H), 5.03 (s, 2H), 3.92 (s, 3H),2.86 (s, 3H), 3.11 (s, 3H)

Melting point: 134-135° C.

Yield: 33%

Example 94 Cyclohexanecarboxylic acid4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-ylester

C₂₉H₂₅F₃N₂O₆S Mw. 586.59

LC/MS purity: 82%, m/z 585 [M−H]⁻, 587 [M+H]⁺ Rt. 4.54 min. (Method A)

Yield: 22%

Example 95N-(3-Fluoro-4-{6-methoxy-7-[3-(tetrahydro-pyran-4-ylamino)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₁H₃₁F₄N₃O₆S Mw. 649.67

LC/MS purity: %, m/z [M−H]⁻, [M+H]⁺ Rt. min. (Method B)

Yield: 17%

Example 96N-{4-[7-(3-Cyclopropylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide

C₂₉H₂₇F₄N₃O₅S Mw. 605.61

LC/MS purity: %, m/z [M−H]⁻, [M+H]⁺ Rt. min. (Method B)

Yield: 21%

Example 97N-{4-[7-(3-Cyclobutylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide

C₃₀H₂₉F₄N₃O₅S Mw. 619.64

LC/MS purity: %, m/z [M−H]⁻, [M+H]⁺ Rt. min. (Method B)

Yield: 16%

Example 98N-(4-{7-[3-(3-tert-Butyl-ureido)-propoxy]-6-methoxy-quinolin-4-yloxy}-3-fluoro-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₁H₃₂F₄N₄O₆S Mw. 664.68

LC/MS purity: 96%, m/z 663 [M−H]⁻, 665 [M+H]⁺ Rt. 3.53 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.04 (bs, 1H), 10 (bs, 1H), 8.46 (d, 1H),8.15 (d, 1H), 7.91 (s, 2H), 7.48 (s, 1H), 7.38 (s, 2H), 7.18 (d, 1H),7.04 (d, 1H), 6.38 (d, 1H), 5.76 (bs, 1H), 5.56 (bs, 1H), 4.15 (bs, 2H),3.92 (s, 3H), 3.15 (bs, 2H), 1.89 (bs, 2H), 1.21 (s, 9H)

Melting point: 106-108° C.

Yield: 15%

Example 99N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₂H₃₃F₄N₃O₅S Mw. 647.69

LC/MS purity: 98%, m/z 646 [M−H]⁻, 648 [M+H]⁺ Rt. 3.36 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.44 (d, 1H), 8.13 (d, 1H), 7.90(d, 1H), 7.75 (m, 2H), 7.48 (s, 1H), 7.38 (s, 1H), 7.18 (t, 1H), 6.97(dd, 1H), 6.84 (d, 1H), 6.35 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 2.99(m, 2H), 2.63 (m, 2H), 2.40 (m, 1H), 2.00 (m, 2H), 1.56 (m, 4H), 1.30(m, 2H), 1.09 (d, 3H).

Melting point: 115-116° C.

Yield: 20%

Example 100N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide

C₂₈H₂₇F₄N₃O₅S Mw. 593.60

LC/MS purity: 100%, m/z 592 [M−H]⁻, 594 [M+H]⁺ Rt. 0.90 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.43 (s, 1H), 8.12 (d, 1H),7.90 (d, 1H), 7.75 (m, 2H), 7.48 (s, 1H), 7.37 (s, 1H), 7.17 (t, 1H),6.96 (d, 1H), 6.84 (d, 1H), 6.35 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H),2.58 (t, 2H), 2.50 (s, 6H), 1.99 (m, 2H)

Melting point: 89-91° C.

Yield: 35%

Example 101N-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide

C₃₀H₃₁F₄N₃O₅S Mw. 621.66

LC/MS purity: %, m/z [M+H]⁺ Rt. min. (Method B)

Yield: 30%

Example 102N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₁H₃₃F₃N₄O₅S Mw. 630.69

LC/MS purity: 98%, m/z 629 [M−H]⁻, 631 [M+H]⁺ Rt. 3.41 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.41 (d, 1H), 8.03 (d, 1H), 7.88(d, 1H) 7.74 (bs, 2H), 7.36 (bs, 2H), 7.26 (t, 1H), 6.91 (d, 1H), 6.78(s, 1H), 6.72 (d, 1H), 6.30 (d, 1H), 4.18 (bs, 2H), 3.87 (s, 3H), 2.36(m, 10H), 2.17 (s, 3H), 1.96 (m, 2H).

Melting point: 155-156° C.

Yield: 27%

Example 103N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide

C₂₉H₃₀FN₃O₇S Mw. 583.64

LC/MS purity: 98%, m/z 582 [M−H]⁻, 584 [M+H]⁺ Rt. 3.46 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.40 (s, 1H), 8.43 (d, 1H), 7.83 (d, 1H),7.62 (t, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.30 (t, 1H), 7.21 (d, 1H),7.13-6.90 (m, 3H), 6.29 (d, 1H), 4.26 (t, 2H), 3.90 (s, 6H), 3.60 (t,4H), 2.78 (t, 2H), 2.52 (t, 4H)

Melting point: 182-183° C.

Yield: 41%

Example 1042,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₂₈H₂₆Cl₂FN₃O₆S Mw. 622.50

LC/MS purity: 98%, m/z 622 [M−H]⁻, 624 [M+H]⁺ Rt. 3.12 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.21 (bs, 1H), 8.44 (s, 1H), 7.66 (m, 2H),7.59 (d, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 7.34 (d, 1H), 7.15 (d, 1H),7.00 (d, 1H), 6.33 (s, 1H), 4.27 (bs, 2H), 3.91 (s, 3H), 3.59 (s, 4H),2.80 (bs, 2H), 2.52 (s, 4H).

Melting point: 210-211° C.

Yield: 54%

Example 105 Thiophene-2-sulfonic acid{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-amide

C₂₆H₂₆FN₃O₆S₂ Mw. 559.64

LC/MS purity: 98%, m/z 558 [M−H]⁻, 560 [M+H]⁺ Rt. 2.85 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.47 (d, 1H), 8.04 (s, 1H),7.70 (s, 2H), 7.48 (s, 1H), 7.43 (s, 1H), 7.30 (t, 1H), 7.13 (d, 1H),6.97 (d, 1H), 6.36 (d, 1H), 4.26 (t, 2H), 3.93 (s, 3H), 3.59 (s, 4H),2.81 (m, 2H), 2.56 (bs, 4H).

Melting point: 146-147° C.

Yield: 55%

Example 1062,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₂₈H₂₆Cl₂FN₃O₆S Mw. 622.50

LC/MS purity: 97%, m/z 622 [M−H]⁻, 624 [M+H]⁺ Rt. 3.28 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.1 (bs, 1H), 8.44 (s, 1H), 8.03 (s, 1H),7.71 (s, 2H), 7.47 (s, 1H), 7.42 (s, 1H), 7.33 (t, 1H), 7.12 (d, 1H),6.99 (d, 1H), 6.34 (s, 1H), 4.27 (bs, 2H), 3.91 (s, 3H), 3.59 (s, 4H),2.80 (bs, 2H), 2.53 (s, 4H)

Melting point: 194-196° C.

Yield: 74%

Example 107 1-Methyl-1H-pyrazole-3-sulfonic acid{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-amide

C₂₆H₂₈FN₅O₆S Mw. 557.60

LC/MS purity: 98%, m/z 556 [M−H]⁻, 558 [M+H]⁺ Rt. 2.66 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.74 (s, 1H), 8.45 (s, 1H), 7.88 (s, 1H),7.49 (s, 1H), 7.43 (s, 1H), 7.36 (t, 1H), 7.20 (d, 1H), 7.07 (d, 1H),6.68 (s, 1H), 6.38 (s, 1H), 4.27 (bs, 2H), 3.91 (s, 6H), 3.59 (s, 4H),2.79 (bs, 2H), 2.53 (s, 4H)

Melting point: 213-214° C.

Yield: 69%

Example 1082-Chloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-benzenesulfonamide

C₂₈H₂₇ClFN₃O₆S Mw. 588.05

LC/MS purity: 96%, m/z 586 [M−H]⁻, 588 [M+H]⁺ Rt. 3.24 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.01 (bs, 1H), 8.43 (s, 1H), 8.01 (d, 1H),7.67 (s, 2H), 7.56 (s, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 7.34 (t, 1H),7.13 (d, 1H), 7.02 (d, 1H), 6.32 (s, 1H), 4.26 (bs, 2H), 3.90 (s, 3H),3.59 (s, 4H), 2.79 (bs, 2H), 2.51 (s, 4H)

Melting point: 180-181° C.

Yield: 76%

Example 109N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-2-nitro-benzenesulfonamide

C₂₈H₂₇FN₄O₈S Mw. 598.61

LC/MS purity: 97%, m/z 597 [M−H]⁻, 599 [M+H]⁺ Rt. 2.88 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.45 (s, 1H), 8.02 (s, 1H), 7.93(s, 1H), 7.83 (s, 2H), 7.48 (s, 1H), 7.43 (s, 1H), 7.32 (t, 1H), 7.11(d, 1H), 6.97 (d, 1H), 6.37 (s, 1H), 4.27 (bs, 2H), 3.92 (s, 3H), 3.59(s, 4H), 2.81 (bs, 2H), 2.54 (s, 4H)

Melting point: 129-131° C.

Yield: 74%

Example 1102,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₁F₃N₄O₅S Mw. 616.66

LC/MS purity: 97%, m/z 615 [M−H]⁻, 617 [M+H]⁺ Rt. 2.77 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 7.6 (t, 1H),7.48 (s, 1H), 7.37 (s, 1H), 7.19 (m, 3H), 7.05 (d, 1H), 6.90 (d, 1H),6.34 (d, 1H), 4.18 (bs, 2H), 3.92 (s, 3H), 2.48 (s, 10H), 2.26 (s, 3H),1.97 (bs, 2H).

Melting point: 199-201° C.

Yield: 41%

Example 111N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-fluoro-benzenesulfonamide

C₃₀H₃₂ClFN₄O₅S Mw. 615.12

LC/MS purity: 95%, m/z 613 [M−H]⁻, 615 [M+H]⁺ Rt. 3.01 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1H), 8.43 (dd, 1H), 7.86 (t, 1H),7.65 (s, 1H), 7.36 (m, 6H), 7.09 (dd, 1H), 6.23 (d, 1H), 4.17 (s, 2H),3.91 (s, 3H), 2.41 (s, 10H), 2.19 (s, 3H), 1.96 (s, 2H).

Melting point: 170-171° C.

Yield: 52%

Example 112N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide

C₃₀H₃₁ClF₂N₄O₅S Mw. 633.11

LC/MS purity: 96%, m/z 631 [M−H]⁻, 633 [M+H]⁺ Rt. 2.94 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.42 (d, 1H), 7.59 (m, 1H),7.48 (s, 1H), 7.40 (m, 2H), 7.37 (s, 1H), 7.20 (m, 2H), 7.03 (d, 1H),6.25 (d, 1H), 4.18 (bs, 2H), 3.92 (s, 3H), 2.49 (s, 10H), 2.28 (s, 3H),1.97 (bs, 2H).

Melting point: 118-121° C.

Yield: 68° A

Example 113 Benzo[b]thiophene-3-sulfonic acid{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide

C₃₂H₃₂FN₃O₅S₂ Mw. 621.75

LC/MS purity: 98%, m/z 620 [M−H]⁻, 622 [M+H]⁺ Rt. 3.56 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (s, 1H), 8.53 (s, 1H), 8.41 (d, 1H),8.26 (d, 1H), 8.08 (d, 1H), 7.52 (m, 4H), 7.35 (s, 1H), 7.20 (t, 1H),7.08 (d, 1H), 6.90 (d, 1H), 4.16 (s, 2H), 3.90 (s, 3H), 2.47 (s, 6H),1.98 (s, 2H), 1.52 (s, 4H), 1.40 (s, 2H).

Melting point: 128-130° C.

Yield: 65%

Example 114 Benzo[b]thiophene-3-sulfonic acid{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide

C₃₁H₃₀FN₃O₆S₂ Mw. 623.72

LC/MS purity: 99%, m/z 622 [M−H]⁻, 624 [M+H]⁺ Rt. 3.54 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.66 (d, 1H), 8.42 (d, 1H), 8.24(d, 1H), 8.12 (d, 1H), 7.56 (m, 2H), 7.44 (s, 1H), 7.37 (s, 1H), 7.28(t, 1H), 7.14 (d, 1H), 6.97 (d, 1H), 6.29 (s, 1H), 4.18 (s, 2H), 3.90(s, 3H), 3.58 (s, 4H), 2.47 (s, 2H), 2.38 (s, 4H), 1.96 (s, 2H).

Melting point: 196-197° C.

Yield: 64%

Example 115

Benzo[b]thiophene-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-loxy}-phenyl)-amide

C₃₃H₃₄FN₃O₅S₂ Mw. 635.78

LC/MS purity: 98%, m/z 634 [M−H]⁻, 636 [M+H]⁺ Rt. 3.81 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.9 (bs, 1H), 8.58 (s, 1H), 8.41 (d, 1H),8.24 (d, 1H), 8.09 (d, 1H), 7.52 (m, 3H), 7.36 (s, 1H), 7.23 (t, 1H),7.09 (d, 1H), 6.93 (d, 1H), 6.29 (s, 1H), 4.17 (s, 2H), 3.90 (s, 3H),2.92 (d, 2H), 2.02 (m, 4H), 1.60 (s, 2H), 1.35 (bs, 1H), 1.11 (m, 4H),0.88 (s, 3H).

Melting point: 132-135° C.

Yield: 61%

Example 116

Benzo[b]thiophene-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₂H₃₃FN₄O₅S₂ Mw. 636.77

LC/MS purity: 98%, m/z 635 [M−H]⁻, 637 [M+H]⁺ Rt. 3.29 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.58 (s, 1H), 8.42 (d, 1H),8.24 (d, 1H), 8.09 (d, 1H), 7.52 (m, 3H), 7.45 (s, 1H), 7.35 (s, 1H),7.09 (d, 1H), 6.93 (d, 1H), 6.29 (s, 1H), 4.16 (s, 2H), 3.90 (s, 3H),2.43 (m, 10H), 2.18 (s, 3H), 1.95 (s, 2H).

Melting point: 112-114° C.

Yield: 73%

Example 117

Benzo[b]thiophene-3-sulfonic acid(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₂H₃₃ClN₄O₅S₂ Mw. 653.22

LC/MS purity: 99%, m/z 651 [M−H]⁻, 653 [M+H]⁺ Rt. 3.36 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.56 (s, 1H), 8.40 (t, 1H), 8.23(d, 1H), 8.09 (d, 1H), 7.52 (m, 2H), 7.45 (s, 1H), 7.35 (s, 1H), 7.24(m, 2H), 7.09 (d, 1H), 6.19 (s, 1H), 4.17 (s, 2H), 3.89 (s, 3H), 2.39(bs, 10H), 2.19 (s, 3H), 1.95 (s, 2H).

Melting point: 98-101° C.

Yield: 75%

Example 118N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide

C₃₀H₃₁ClF₂N₄O₅S Mw. 633.11

LC/MS purity: 99%, m/z 631 [M−H]⁻, 633 [M+H]⁺ Rt. 2.84 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.42 (s, 1H), 7.62 (s, 1H),7.48 (s, 1H), 7.37 (s, 1H), 7.23 (m, 4H), 7.06 (d, 1H), 6.24 (s, 1H),4.18 (s, 2H), 3.91 (s, 3H), 2.49 (s, 10H), 2.29 (s, 3H), 1.97 (s, 2H).

Melting point: 122-124° C.

Yield: 48%

Example 1192,6-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₁Cl₃N₄O₅S Mw. 666.02

LC/MS purity: 98%, m/z 665 [M−H]⁻, 667 [M+H]⁺ Rt. 3.12 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.41 (s, 1H), 7.58 (s, 2H), 7.47(s, 2H), 7.37 (s, 1H), 7.25 (s, 2H), 7.04 (s, 1H), 6.23 (s, 1H), 4.18(s, 2H), 3.91 (s, 3H), 2.50 (s, 10H), 2.29 (s, 3H), 1.97 (s, 2H).

Melting point: 171-172° C.

Yield: 34%

Example 120(3-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-carbamicacid tert-butyl ester

C₃₁H₃₁F₄N₃O₇S Mw. 665.66

LC/MS purity: 100%, m/z 664 [M−H]⁻, 666 [M+H]⁺ Rt. 3.66 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.45 (s, 1H), 8.15 (d, 1H), 8.02(d, 1H), 7.90 (bs, 2H), 7.47 (s, 1H), 7.37 (bs, 2H), 7.16 (d, 1H), 7.03(d, 1H), 6.88 (bs, 1H), 6.36 (d, 1H), 4.16 (bs, 2H), 3.92 (s, 3H), 3.13(bs, 2H), 1.93 (bs, 2H), 1.38 (s, 9H).

Melting point: 80-82° C.

Yield: 84%

Example 121(3-{-4-[4-(2,5-Difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-carbamicacid tert-butyl ester

C₃₀H₃₀F₃N₃O₇S Mw. 633.64

LC/MS purity: 99%, m/z 632 [M−H]⁻, 634 [M+H]⁺ Rt. 3.57 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.45 (d, 1H), 7.60 (m, 3H), 7.48(s, 1H), 7.37 (bs, 2H), 7.19 (d, 1H), 7.05 (d, 1H), 6.88 (bs, 1H), 6.35(d, 1H), 4.16 (bs, 2H), 3.92 (s, 3H), 3.16 (bs, 2H), 1.93 (bs, 2H), 1.38(s, 9H).

Melting point: 115-118° C.

Yield: 78%

Example 122N-{4-[7-(3-Amino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,5-difluoro-benzenesulfonamidehydrochloride

C₂₅H₂₂F₃N₃O₅S.HCl Mw. 533.53

LC/MS purity: 99%, m/z 532 [M−H]⁻, 534 [M+H]⁺ Rt. 2.71 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.37 (s, 1H), 8.77 (bs, 1H), 8.09 (bs, 2H),7.61 (m, 4H), 7.28 (d, 1H), 7.15 (d, 1H), 6.85 (bs, 1H), 4.33 (bs, 2H),4.02 (s, 3H), 3.57 (s, 2H), 3.01 (bs, 2H), 2.19 (bs, 2H).

Melting point: 188-190° C.

Yield: 85%

Example 1232,5-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₂F₂N₄O₅S Mw. 598.67

LC/MS purity: 98%, m/z 597 [M−H]⁻, 599 [M+H]⁺ Rt. 2.38 min. (Method A)

LC/MS purity: 99%, m/z 631 [M−H]⁻, 633 [M+H]⁺ Rt. 2.84 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.39 (d, 1H), 7.42 (bs, 2H),7.35 (m, 3H), 7.17 (t, 1H), 6.82 (d, 1H), 6.77 (s, 1H), 6.57 (d, 1H),6.29 (d, 1H), 4.18 (bs, 2H), 3.90 (s, 3H), 2.40 (s, 10H), 2.16 (s, 3H),1.96 (s, 2H).

Melting point: 186-188° C.

Yield: 52%

Example 1242,5-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₁Cl₃N₄O₅S Mw. 666.02

LC/MS purity: 99%, m/z 664 [M−H]⁻, 666 [M+H]⁺ Rt. 3.39 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.42 (d, 1H), 7.97 (s, 1H),7.62 (bs, 2H), 7.48 (s, 1H), 7.37 (s, 1H), 7.19 (m, 2H), 7.00 (d, 1H),6.25 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.49 (s, 10H), 2.32 (s, 3H),1.97 (s, 2H).

Melting point: 144-145° C.

Yield: 66%

Example 1252,6-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₂F₂N₄O₅S Mw. 598.67

LC/MS purity: 98%, m/z 597 [M−H]⁻, 599 [M+H]⁺ Rt. 3.04 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.43 (d, 1H), 7.64 (m, 1H),7.40 (s, 1H), 7.37 (s, 1H), 7.31 (t, 1H), 7.18 (t, 2H), 6.97 (d, 1H),6.88 (s, 1H), 6.80 (s, 1H), 6.20 (d, 1H), 4.18 (t, 2H), 3.89 (s, 3H),2.46 (t, 2H), 2.41 (s, 8H), 2.20 (s, 3H), 1.96 (t, 2H).

Melting point: 171-172° C.

Yield: 58%

Example 126N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide

C₃₁H₃₃F₃N₄O₆S Mw. 646.69

LC/MS purity: 99%, m/z 645 [M−H]⁻, 647 [M+H]⁺ Rt. 3.58 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.43 (d, 1H), 7.88 (d, 1H), 7.72(t, 1H), 7.38 (m, 5H), 6.95 (d, 1H), 6.70 (m, 2H), 6.26 (d, 1H), 4.18(t, 2H), 3.88 (s, 3H), 2.44 (m, 10H), 2.17 (s, 3H), 1.96 (t, 2H).

Melting point: 164-166° C.

Yield: 60%

Example 1272,5-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₂Cl₂N₄O₅S Mw. 631.58

LC/MS purity: 99%, m/z 629 [M−H]⁻, 631 [M+H]⁺ Rt. 3.45 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1H), 8.43 (d, 1H), 7.90 (m, 1H),7.65 (m, 2H), 7.40 (s, 1H), 7.37 (s, 1H), 7.31 (t, 1H), 6.96 (d, 1H),6.80 (m, 2H), 6.24 (d, 1H), 4.18 (t, 2H), 3.89 (s, 3H), 2.47 (m, 10H),2.24 (s, 3H), 1.98 (t, 2H).

Melting point: 111-113° C.

Yield: 55%

Example 1282,6-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₀H₃₂Cl₂N₄O₅S Mw. 631.58

LC/MS purity: 99%, m/z 629 [M−H]⁻, 631 [M+H]⁺ Rt. 3.35 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.42 (d, 1H), 7.52 (m, 3H),7.37 (s, 2H), 7.30 (t, 1H), 6.93 (d, 1H), 6.81 (s, 1H), 6.79 (d, 1H),6.23 (d, 1H), 4.16 (t, 2H), 3.87 (s, 3H), 2.45 (m, 10H), 2.19 (s, 3H),1.97 (m, 2H).

Melting point: 111-112° C.

Yield: 51%

Example 129 Thiophene-2-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₂N₄O₅S₂ Mw. 568.71

LC/MS purity: 97%, m/z 567 [M−H]⁻, 569 [M+H]⁺ Rt. 2.97 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.47 (d, 1H), 7.88 (d, 1H),7.41 (m, 4H), 7.10 (d, 1H), 6.98 (d, 1H), 6.90 (s, 2H), 6.32 (d, 1H),4.18 (bs, 2H), 3.90 (s, 3H), 2.40 (m, 10H), 2.17 (s, 3H), 1.96 (bs, 2H).

Melting point: 188-189° C.

Yield: 31%

Example 130 5-Chloro-thiophene-2-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₁ClN₄O₅S₂ Mw. 603.16

LC/MS purity: 99%, m/z 601 [M−H]⁻, 603 [M+H]⁺ Rt. 3.05 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.47 (s, 1H), 7.36 (m, 4H), 7.14(d, 1H), 7.00 (s, 1H), 6.86 (s, 2H), 6.36 (d, 1H), 4.18 (bs, 2H), 3.90(s, 3H), 2.45 (m, 10H), 2.22 (s, 3H), 1.97 (bs, 2H).

Melting point: 162-163° C.

Yield: 52%

Example 131 5-Methyl-thiophene-2-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₄N₄O₅S₂ Mw. 582.74

LC/MS purity: 98%, m/z 581 [M−H]⁻, 583 [M+H]⁺ Rt. 3.21 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.47 (d, 1H), 7.42 (s, 1H),7.38 (s, 1H), 7.34 (t, 1H), 7.26 (d, 1H), 7.01 (d, 1H), 6.85 (m, 3H),6.36 (d, 1H), 4.18 (t, 2H), 3.90 (s, 3H), 2.40 (m, 13H), 2.16 (s, 3H),1.96 (m, 2H).

Melting point: 147-149° C.

Yield: 33%

Example 132N-[5-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-4-methyl-thiazol-2-yl]-acetamide

C₃₀H₃₆N₆O₆S₂ Mw. 640.78

LC/MS purity: 98%, m/z 639 [M−H]⁻, 641 [M+H]⁺ Rt. 2.68 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 12.2 (bs, 1H), 8.44 (d, 1H), 7.38 (m, 3H),7.03 (d, 1H), 6.92 (s, 2H), 6.30 (d, 1H), 4.19 (bs, 2H), 3.90 (s, 3H),2.40 (m, 16H), 2.16 (s, 3H), 1.96 (m, 2H).

Melting point: 148-150° C.

Yield: 36%

Example 133

Thiophene-3-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₂N₄O₅S₂ Mw. 568.71

LC/MS purity: 98%, m/z 567 [M−H]⁻, 569 [M+H]⁺ Rt. 3.11 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.47 (d, 1H), 8.10 (s, 1H),7.70 (d, 1H), 7.38 (m, 3H), 7.22 (d, 1H), 7.06 (d, 1H), 6.88 (s, 2H),6.30 (d, 1H), 4.18 (t, 2H), 3.90 (s, 3H), 2.45 (m, 10H), 2.15 (s, 3H),1.97 (m, 2H).

Melting point: 176-178° C.

Yield: 41%

Example 134 2,5-Dichloro-thiophene-3-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₀Cl₂N₄O₅S₂ Mw. 637.60

LC/MS purity: 98%, m/z 635 [M−H]⁻, 637 [M+H]⁺ Rt. 3.19 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.46 (d, 1H), 7.43 (s, 1H),7.37 (s, 1H), 7.31 (t, 1H), 7.17 (s, 1H), 6.94 (d, 1H), 6.80 (m, 2H),6.36 (d, 1H), 4.18 (t, 2H), 3.91 (s, 3H), 2.44 (m, 10H), 2.22 (s, 3H),1.97 (m, 2H).

Melting point: 177-178° C.

Yield: 35%

Example 1353-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylicacid methyl ester

C₃₀H₃₄N₄O₇S₂ Mw. 626.75

LC/MS purity: 99%, m/z 625 [M−H]⁻, 627 [M+H]⁺ Rt. 2.37 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.45 (s, 1H), 7.90 (s, 1H),7.37 (m, 4H), 6.98 (d, 1H), 6.85 (bs, 2H), 6.00 (s, 1H), 4.18 (bs, 2H),3.89 (s, 3H), 3.80 (s, 3H), 2.38 (m, 10H), 2.15 (s, 3H), 1.96 (bs, 2H).

Melting point: 84-86° C.

Yield: 33%

Example 136 Benzo[b]thiophene-3-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₂H₃₄N₄O₅S₂ Mw. 618.77

LC/MS purity: 98%, m/z 617 [M−H]⁻, 619 [M+H]⁺ Rt. 3.42 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.7 (bs, 1H), 8.46 (s, 1H), 8.39 (d, 1H),8.20 (d, 1H), 8.09 (d, 1H), 7.48 (bs, 2H), 7.36 (s, 2H), 7.28 (t, 1H),7.01 (d, 1H), 6.80 (m, 2H), 6.13 (d, 1H), 4.17 (bs, 2H), 3.87 (s, 3H),2.40 (m, 10H), 2.16 (s, 3H), 1.95 (bs, 2H).

Melting point: 91-93° C.

Yield: 42%

Example 137

Furan-2-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₂N₄O₆S Mw. 552.65

LC/MS purity: 98%, m/z 551 [M−H]⁻, 553 [M+H]⁺ Rt. 2.71 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.49 (d, 1H), 7.90 (s, 1H),7.40 (m, 3H), 7.04 (m, 2H), 6.90 (m, 2H), 6.62 (s, 1H), 6.39 (d, 1H),4.19 (bs, 2H), 3.90 (s, 3H), 2.41 (m, 10H), 2.20 (s, 3H), 1.96 (bs, 2H).

Melting point: 176-177° C.

Yield: 39%

Example 138 3,5-Dimethyl-isoxazole-4-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₅N₅O₆S Mw. 581.69

LC/MS purity: 99%, m/z 580 [M−H]⁻, 582 [M+H]⁺ Rt. 2.82 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.47 (d, 1H), 7.40 (m, 3H), 6.95(m, 2H), 6.82 (s, 1H), 6.38 (d, 1H), 4.19 (bs, 2H), 3.90 (s, 3H), 2.40(m, 10H), 2.22 (s, 6H), 2.19 (s, 3H), 1.96 (bs, 2H).

Melting point: 200-202° C.

Yield: 38%

Example 139 1-Methyl-1H-pyrazole-3-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₄N₆O₅S Mw. 566.68

LC/MS purity: 98%, m/z 565 [M−H]⁻, 567 [M+H]⁺ Rt. 2.72 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.48 (d, 1H), 7.82 (s, 1H),7.43 (s, 1H), 7.38 (s, 1H), 7.33 (t, 1H), 7.02 (s, 1H), 6.96 (s, 1H),6.84 (d, 1H), 6.55 (d, 1H), 6.38 (d, 1H), 4.18 (bs, 2H), 3.91 (s, 3H),3.84 (s, 3H), 2.35 (m, 10H), 2.15 (s, 3H), 1.96 (bs, 2H).

Melting point: 87-89° C.

Yield: 26%

Example 140 1-Ethyl-1H-pyrazole-4-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₆N₆O₅S Mw. 580.71

LC/MS purity: 98%, m/z 579[M−H]⁻, 581 [M+H]⁺ Rt. 2.91 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.46 (d, 1H), 8.25 (s, 1H),7.66 (s, 1H), 7.44 (s, 1H), 7.38 (m, 2H), 7.06 (d, 1H), 6.91 (m, 2H),6.38 (d, 1H), 4.15 (bs, 2H), 3.91 (s, 3H), 2.40 (m, 12H), 2.16 (s, 3H),1.96 (bs, 2H), 1.32 (t, 3H).

Melting point: 87-90° C.

Yield: 38%

Example 141 2-Methyl-1H-imidazole-4-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₄N₆O₅S Mw. 566.68

LC/MS purity: 96%, m/z 565 [M−H]⁻, 567 [M+H]⁺ Rt. 2.70 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 12.4 (bs, 1H), 10.2 (bs, 1H), 8.47 (d, 1H),7.59 (bs, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.32 (t, 1H), 7.05 (d, 1H),6.98 (s, 1H), 6.82 (bs, 1H), 6.35 (d, 1H), 4.18 (bs, 2H), 3.91 (s, 3H),2.45 (m, 10H), 2.24 (s, 3H), 2.15 (s, 3H), 1.96 (bs, 2H).

Melting point: 118-120° C.

Yield: 33%

Example 142

Cyclopropanesulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₇H₃₄N₄O₅S Mw. 526.65

LC/MS purity: 99%, m/z 525 [M−H]⁻, 527 [M+H]⁺ Rt. 2.99 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.50 (d, 1H), 7.47 (s, 1H), 7.43(d, 1H), 7.38 (s, 1H), 7.16 (d, 1H), 7.07 (s, 1H), 6.97 (d, 1H), 6.53(d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.67 (m, 1H), 2.40 (m, 10H), 2.15(s, 3H), 1.96 (m, 2H), 0.94 (m, 4H).

Melting point: 150-152° C.

Yield: 43%

Example 143 2-Phenyl-ethenesulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)amide

C₃₂H₃₆N₄O₅S Mw. 588.73

LC/MS purity: 99%, m/z 587 [M−H]⁻, 589 [M+H]⁺ Rt. 3.41 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.27 (d, 1H), 7.66 (s, 1H),7.64 (s, 1H), 7.40 (m, 7H), 7.26 (d, 1H), 7.12 (d, 1H), 7.00 (s, 1H),6.89 (d, 1H), 6.39 (d, 1H), 4.17 (t, 2H), 3.89 (s, 3H), 2.40 (m, 10H),2.15 (s, 3H), 1.95 (m, 2H).

Melting point: 85-87° C.

Yield: 39%

Example 144

Thiophene-2-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₂FN₃O₅S₂ Mw. 585.72

LC/MS purity: 98%, m/z 584 [M−H]⁻, 586 [M+H]⁺ Rt. 3.08 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.45 (d, 1H), 7.78 (d, 1H),7.49 (s, 2H), 7.38 (s, 1H), 7.24 (t, 1H), 7.07 (m, 2H), 6.92 (d, 1H),6.36 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.94 (m, 2H), 2.50 (m, 2H),2.30 (m, 1H), 1.96 (m, 2H), 1.50 (m, 4H), 1.27 (m, 2H), 1.05 (d, 3H).

Melting point: 117-119° C.

Yield: 47%

Example 145 5-Chloro-thiophene-2-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)amide

C₂₉H₃₁ClFN₃O₅S₂ Mw. 620.16

LC/MS purity: 99%, 618 m/z [M−H]⁻, 620 [M+H]⁺ Rt. 3.24 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 7.50 (s, 1H),7.38 (s, 1H), 7.18 (d, 1H), 7.09 (t, 1H), 7.03 (d, 1H), 6.83 (d, 1H),6.77 (d, 1H), 6.37 (d, 1H), 4.19 (t, 2H), 3.93 (s, 3H), 2.97 (m, 2H),2.70 (m, 2H), 2.36 (m, 1H), 1.99 (m, 2H), 1.56 (m, 4H), 1.29 (m, 2H),1.08 (d, 3H).

Melting point: 118-120° C.

Yield: 31

Example 146 2,4-Dichloro-thiophene-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₀Cl₂FN₃O₅S₂ Mw. 654.61

LC/MS purity: 99%, m/z 652 [M−H]⁻, 654 [M+H]⁺ Rt. 3.39 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.45 (d, 1H), 7.51 (s, 1H), 7.39(s, 1H), 7.15 (s, 1H), 7.10 (d, 1H), 6.93 (d, 1H), 6.78 (d, 1H), 6.39(d, 1H), 4.21 (t, 2H), 3.93 (s, 3H), 3.04 (m, 2H), 2.71 (m, 2H), 2.49(m, 1H), 2.03 (m, 2H), 1.60 (m, 4H), 1.34 (m, 2H), 1.11 (d, 3H).

Melting point: 131-132° C.

Yield: 39%

Example 147 Benzo[b]thiophene-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₃H₃₄FN₃O₅S₂ Mw. 635.78

LC/MS purity: 99%, m/z 634 [M−H]⁻, 636 [M+H]⁺ Rt. 3.52 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.53 (s, 1H), 8.41 (d, 1H),8.25 (d, 1H), 8.09 (d, 1H), 7.50 (m, 2H), 7.45 (s, 1H), 7.37 (s, 1H),7.20 (t, 1H), 7.07 (d, 1H), 6.90 (d, 1H), 6.29 (d, 1H), 4.17 (t, 2H),3.90 (s, 3H), 2.90 (m, 2H), 2.49 (m, 2H), 2.28 (m, 1H), 1.94 (m, 2H),1.53 (m, 4H), 1.26 (m, 2H), 1.04 (d, 3H).

Melting point: 120-122° C.

Yield: 45%

Example 148 Furan-2-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₂FN₃O₆S Mw. 569.65

LC/MS purity: 98%, m/z 568 [M−H]⁻, 570 [M+H]⁺ Rt. 2.88 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.45 (d, 1H), 7.82 (s, 1H), 7.50(s, 1H), 7.39 (s, 1H), 7.20 (t, 1H), 7.03 (d, 1H), 6.95 (s, 1H), 6.88(d, 1H), 6.56 (s, 1H), 6.38 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H), 2.99(m, 2H), 2.63 (m, 2H), 2.40 (m, 1H), 2.00 (m, 2H), 1.55 (m, 4H), 1.30(m, 2H), 1.09 (d, 3H).

Melting point: 118-119° C.

Yield: 34

Example 149 2-Methyl-1H-imidazole-4-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₄FN₅O₅S Mw. 583.68

LC/MS purity: 99%, m/z 582 [M−H]⁻, 584 [M+H]⁺ Rt. 2.81 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 12.5 (bs, 1H), 10.6 (bs, 1H), 8.44 (d, 1H),7.75 (s, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.32 (t, 1H), 7.19 (d, 1H),7.04 (d, 1H), 6.37 (d, 1H), 4.17 (t, 2H), 3.92 (s, 3H), 2.84 (m, 2H),2.42 (m, 1H), 2.28 (s, 3H), 2.11 (m, 2H), 1.91 (m, 2H), 1.50 (m, 4H),1.20 (m, 2H), 0.99 (d, 3H).

Melting point: 219-220° C.

Yield: 26%

Example 150 1-Methyl-1H-pyrazole-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₄FN₅O₅S Mw. 583.68

LC/MS purity: 98%, m/z 582 [M−H]⁻, 584 [M+H]⁺ Rt. 2.56 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.7 (bs, 1H), 8.45 (d, 1H), 7.85 (s, 1H),7.48 (s, 1H), 7.38 (s, 1H), 7.31 (t, 1H), 7.16 (d, 1H), 7.01 (d, 1H),6.64 (d, 1H), 6.38 (d, 1H), 4.17 (t, 2H), 3.92 (s, 3H), 3.90 (s, 3H),2.86 (m, 2H), 2.42 (m, 1H), 2.32 (s, 1H), 2.13 (m, 2H), 1.92 (m, 1H),1.49 (m, 4H), 1.23 (m, 2H), 1.00 (d, 3H).

Melting point: 175-176° C.

Yield: 35%

Example 1512,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂F₃N₃O₅S Mw. 615.67

LC/MS purity: 97%, m/z 614 [M−H]⁻, 616 [M+H]⁺ Rt. 3.07 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.44 (d, 1H), 7.56 (t, 1H), 7.49(s, 1H), 7.38 (m, 3H), 7.14 (t, 1H), 6.97 (d, 1H), 6.82 (d, 1H), 6.36(s, 1H), 4.20 (t, 2H), 3.92 (s, 3H), 3.05 (m, 2H), 2.72 (m, 2H), 2.50(m, 1H), 2.03 (m, 2H), 1.60 (m, 4H), 1.34 (m, 2H), 1.11 (d, 3H).

Melting point: 120-122° C.

Yield: 33%

Example 1522,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂F₃N₃O₅S Mw. 615.67

LC/MS purity: 100%, m/z 614[M−H]⁻, 616 [M+H]⁺ Rt. 3.03 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.43 (d, 1H), 7.49 (m, 2H), 7.38(s, 1H), 7.11 (m, 3H), 6.97 (d, 1H), 6.79 (d, 1H), 6.34 (d, 1H), 4.19(m, 2H), 3.92 (s, 3H), 2.97 (m, 2H), 2.61 (m, 2H), 2.46 (m, 1H), 2.00(m, 2H), 1.58 (m, 4H), 1.30 (m, 2H), 1.08 (d, 3H).

Melting point: 132-134° C.

Yield: 26%

Example 153N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide

C₃₂H₃₃F₄N₃O₆S Mw. 663.69

LC/MS purity: 98%, m/z 662 [M−H]⁻, 664 [M+H]⁺ Rt. 3.52 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.43 (d, 1H), 7.99 (d, 1H),7.68 (t, 1H), 7.48 (m, 3H), 7.38 (s, 1H), 7.19 (t, 1H), 7.02 (d, 1H),6.85 (d, 1H), 6.33 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 2.96 (m, 2H),2.55 (m, 2H), 2.36 (m, 1H), 1.98 (t, 2H), 1.55 (m, 4H), 1.29 (m, 2H),1.07 (d, 3H).

Melting point: 90-92° C.

Yield: 29%

Example 1542,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂Cl₂FN₃O₅S Mw. 648.58

LC/MS purity: 98%, m/z 646 [M−H]⁻, 648 [M+H]⁺ Rt. 3.39 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.44 (d, 1H), 7.96 (s, 1H), 7.55(s, 2H), 7.50 (s, 1H), 7.39 (s, 1H), 7.12 (t, 1H), 6.92 (d, 1H), 6.80(d, 1H), 6.35 (d, 1H), 4.21 (t, 2H), 3.92 (s, 3H), 3.01 (m, 2H), 2.72(m, 2H), 2.50 (m, 1H), 2.04 (m, 2H), 1.58 (m, 4H), 1.34 (m, 2H), 1.13(d, 3H).

Melting point: 128-130° C.

Yield: 37%

Example 1553-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenylsulfamoyl}-thiophene-2-carboxylicacid methyl ester

C₃₀H₃₂FN₃O₇S₂ Mw. 629.73

LC/MS purity: 97%, m/z 628 [M−H]⁻, 630 [M+H]⁺ Rt. 3.38 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.45 (d, 1H), 7.94 (d, 1H),7.47 (m, 2H), 7.38 (s, 1H), 7.30 (t, 1H), 7.11 (d, 1H), 6.97 (d, 1H),6.36 (dd, 1H), 4.20 (t, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.45 (m, 6H),1.98 (m, 2H), 1.53 (bs, 4H), 1.40 (m, 2H)

Melting point: 138-139° C.

Yield: 26%

Example 1563-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylicacid methyl ester

C₃₁H₃₄FN₃O₇S₂ Mw. 643.75

LC/MS purity: 99%, m/z 642 [M−H]⁻, 644 [M+H]⁺ Rt. 3.67 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.45 (d, 1H), 7.95 (d, 1H),7.47 (bs, 2H), 7.37 (s, 1H), 7.30 (t, 1H), 7.11 (d, 1H), 6.97 (d, 1H),6.36 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 2.91 (m, 2H),2.55 (m, 2H), 2.00 (m, 4H), 1.60 (m, 2H), 1.35 (bs, 1H), 1.16 (m, 2H),0.89 (d, 3H)

Melting point: 139-141° C.

Yield: 29%

Example 1573-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenylsulfamoyl}-thiophene-2-carboxylicacid methyl ester

C₂₉H₃₀FN₃O₈S₂ Mw. 631.70

LC/MS purity: 98%, m/z 630[M−H]⁻, 632 [M+H]⁺ Rt. 3.33 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.45 (d, 1H), 7.98 (d, 1H),7.50 (d, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.34 (t, 1H), 7.14 (d, 1H),7.01 (d, 1H), 6.36 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 3.89 (s, 3H),3.58 (m, 4H), 2.47 (m, 2H), 2.39 (m, 4H), 1.97 (m, 2H)

Melting point: 167-168° C.

Yield: 31%

Example 1583-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylicacid methyl ester

C₃₀H₃₃FN₄O₇S₂ Mw. 644.74

LC/MS purity: 98%, m/z 643 [M−H]⁻, 645 [M+H]⁺ Rt. 3.13 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.45 (d, 1H), 7.95 (d, 1H),7.47 (s, 2H), 7.37 (s, 1H), 7.31 (t, 1H), 7.12 (d, 1H), 6.98 (d, 1H),6.36 (d, 1H), 4.17 (t, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 2.42 (m, 10H),2.18 (s, 3H), 1.95 (m, 2H)

Melting point: 146-148° C.

Yield: 41%

Example 159 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide

C₃₀H₃₆FN₅O₅S Mw. 597.71

LC/MS purity: 97%, m/z 596 [M−H]⁻, 598 [M+H]⁺ Rt. 3.17 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.46 (d, 1H), 7.48 (s, 1H),7.37 (s, 1H), 7.36 (t, 1H), 7.08 (d, 1H), 6.97 (d, 1H), 6.37 (d, 1H),4.18 (t, 2H), 3.92 (s, 3H), 3.66 (s, 3H), 2.85 (d, 2H), 2.43 (m, 2H),2.38 (m, 5H), 2.21 (s, 3H), 1.95 (m, 2H), 1.50 (bs, 4H), 1.39 (m, 2H)

Melting point: 96-98° C.

Yield: 51%

Example 160 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₁H₃₈FN₅O₅S Mw. 611.74

LC/MS purity: 98%, m/z 610 [M−H], 612 [M+H]⁺ Rt. 3.42 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.46 (d, 1H), 7.48 (s, 1H),7.38 (s, 1H), 7.37 (t, 1H), 7.09 (d, 1H), 6.99 (d, 1H), 6.37 (d, 1H),4.17 (t, 2H), 3.92 (s, 3H), 3.67 (s, 3H), 2.85 (d, 2H), 2.45 (m, 2H),2.38 (m, 3H), 2.22 (s, 3H), 1.96 (m, 4H), 1.58 (m, 2H), 1.32 (m, 1H),1.23 (m, 2H), 0.88 (d, 3H)

Melting point: 88-90° C.

Yield: 36%

Example 161 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide

C₂₉H₃₄FN₅O₆S Mw. 599.68

LC/MS purity: 98%, m/z 598 [M−H]⁻, 600 [M+H]⁺ Rt. 3.11 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.46 (d, 1H), 7.48 (s, 1H),7.39 (s, 1H), 7.37 (t, 1H), 7.09 (d, 1H), 6.99 (d, 1H), 6.37 (d, 1H),4.19 (t, 2H), 3.91 (s, 3H), 3.67 (s, 3H), 3.58 (bs, 4H), 2.47 (m, 2H),2.38 (bs, 7H), 2.22 (s, 3H), 1.97 (m, 2H)

Melting point: 163-164° C.

Yield: 49%

Example 162 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₃₀H₃₇FN₆O₅S Mw. 612.72

LC/MS purity: 98%, m/z 611 [M−H]⁻, 613 [M+H]⁺ Rt. 2.89 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.46 (d, 1H), 7.48 (s, 1H),7.37 (s, 1H), 7.36 (t, 1H), 7.08 (d, 1H), 6.97 (d, 1H), 6.37 (d, 1H),4.18 (t, 2H), 3.92 (s, 3H), 3.66 (s, 3H), 2.45 (m, 2H), 2.38 (bs, 7H),2.33 (bs, 4H), 2.21 (s, 3H), 2.15 (s, 3H), 1.95 (m, 2H)

Melting point: 80-81° C.

Yield: 37%

Example 163 1-Methyl-1H-pyrazole-3-sulfonic acid{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide

C₂₈H₃₂FN₅O₅S Mw. 569.66

LC/MS purity: 99%, m/z 568 [M−H]⁻, 570 [M+H]⁺ Rt. 2.56 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.45 (d, 1H), 7.86 (d, 1H),7.49 (s, 1H), 7.38 (s, 1H), 7.33 (t, 1H), 7.18 (d, 1H), 7.03 (d, 1H),6.66 (d, 1H), 6.38 (d, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 3.90 (s, 3H),2.49 (m, 2H), 2.39 (bs, 4H), 1.96 (m, 2H), 1.50 (bs, 4H), 1.39 (m, 2H)

Melting point: 167-168° C.

Yield: 61%

Example 164 1-Methyl-1H-pyrazole-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₄FN₅O₅S Mw. 583.68

LC/MS purity: 98%, m/z 582 [M−H]⁻, 584 [M+H]⁺ Rt. 3.02 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.45 (d, 1H), 7.85 (s, 1H),7.48 (s, 1H), 7.37 (s, 1H), 7.32 (t, 1H), 7.16 (d, 1H), 7.02 (d, 1H),6.65 (s, 1H), 6.38 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 3.90 (s, 3H),2.86 (m, 2H), 2.47 (m, 2H), 1.93 (m, 4H), 1.58 (m, 2H), 1.32 (m, 1H),1.12 (m, 2H), 0.88 (d, 3H)

Melting point: 165-166° C.

Yield: 40%

Example 165 1-Methyl-1H-pyrazole-3-sulfonic acid{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide

C₂₇H₃₀FN₅O₆S Mw. 571.63

LC/MS purity: 98%, m/z 570 [M−H]⁻, 572 [M+H]⁺ Rt. 2.74 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.45 (d, 1H), 7.86 (d, 1H),7.49 (s, 1H), 7.39 (s, 1H), 7.33 (t, 1H), 7.18 (dd, 1H), 7.04 (d, 1H),6.66 (d, 1H), 6.38 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 3.90 (s, 3H),3.58 (m, 4H), 2.47 (m, 2H), 2.39 (m, 4H), 1.97 (m, 2H)

Melting point: 198-199° C.

Yield: 53%

Example 166 1-Methyl-1H-pyrazole-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₃FN₆O₅S Mw. 584.67

LC/MS purity: 97%, 584 m/z [M−H]⁻, 586 [M+H]⁺ Rt. 2.51 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.45 (d, 1H), 7.86 (d, 1H),7.48 (s, 1H), 7.37 (s, 1H), 7.32 (t, 1H), 7.17 (dd, 1H), 7.03 (d, 1H),6.66 (d, 1H), 6.38 (d, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 3.90 (s, 3H),2.46 (m, 2H), 2.38 (m, 8H), 2.15 (s, 3H), 1.95 (m, 2H)

Melting point: 157-159° C.

Yield: 74%

Example 167 2-Methyl-3H-imidazole-4-sulfonic acid{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide

C₂₈H₃₂FN₅O₅S Mw. 569.66

LC/MS purity: 96%, m/z 568[M−H]⁻, 570 [M+H]⁺ Rt. 2.79 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 12.3 (bs, 1H), 10.6 (bs, 1H), 8.44 (d, 1H),7.72 (bs, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.18 (d, 1H),7.02 (d, 1H), 6.37 (d, 1H), 4.17 (t, 2H), 3.92 (s, 3H), 2.42 (m, 2H),2.40 (bs, 4H), 2.28 (s, 3H), 1.94 (m, 2H), 1.50 (bs, 4H), 1.39 (m, 2H)

Melting point: 160-163° C.

Yield: 26%

Example 168 2-Methyl-3H-imidazole-4-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₉H₃₄FN₅O₅S Mw. 583.68

LC/MS purity: 98%, m/z 582 [M−H]⁻, 584 [M+H]⁺ Rt. 3.02 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 12.4 (bs, 1H), 10.7 (bs, 1H), 8.44 (d, 1H),7.72 (bs, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.19 (d, 1H),7.03 (d, 1H), 6.37 (d, 1H), 4.17 (t, 2H), 3.92 (s, 3H), 2.84 (m, 2H),2.44 (m, 2H), 2.38 (s, 3H), 1.95 (m, 2H), 1.88 (m, 2H), 1.57 (m, 2H),1.33 (m, 1H), 1.15 (m, 2H), 0.88 (d, 3H)

Melting point: 225-226° C.

Yield: 30%

Example 169 2-Methyl-3H-imidazole-4-sulfonic acid{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide

C₂₇H₃₀FN₅O₆S Mw. 571.63

LC/MS purity: 99%, m/z 570 [M−H]⁻, 572 [M+H]⁺ Rt. 2.73 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 12.4 (bs, 1H), 10.6 (bs, 1H), 8.45 (d, 1H),7.72 (bs, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.32 (t, 1H), 7.21 (d, 1H),7.05 (d, 1H), 6.37 (d, 1H), 4.19 (t, 2H), 3.93 (s, 3H), 3.58 (m, 4H),2.47 (m, 2H), 2.39 (s, 4H), 2.28 (s, 3H), 1.97 (t, 2H)

Melting point: 252-254° C.

Yield: 38%

Example 170 2-Methyl-3H-imidazole-4-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide

C₂₈H₃₃FN₆O₅S Mw. 584.67

LC/MS purity: 99%, m/z 583 [M−H]⁻, 585 [M+H]⁺ Rt. 2.52 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 12.4 (bs, 1H), 10.6 (bs, 1H), 8.44 (d, 1H),7.73 (bs, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.31 (t, 1H), 7.18 (d, 1H),7.03 (d, 1H), 6.37 (d, 1H), 4.17 (t, 2H), 3.92 (s, 3H), 2.45 (m, 2H),2.39 (bs, 4H), 2.32 (bs, 4H), 2.28 (s, 3H), 2.14 (s, 3H), 1.85 (m, 2H)

Melting point: 215-217° C.

Yield: 32%

Example 1712,5-Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide

C₃₂H₃₅F₂N₃O₅S Mw. 611.71

LC/MS purity: 97%, m/z 610 [M−H]⁻, 612 [M+H]⁺ Rt. 3.76 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.7 (bs, 1H), 8.40 (d, 1H), 7.55 (m, 3H),7.51 (s, 1H), 7.36 (m, 1H), 7.05 (m, 3H), 6.17 (d, 1H), 4.17 (t, 2H),3.92 (s, 3H), 2.89 (m, 2H), 2.01 (s, 3H), 1.98 (m, 4H), 1.59 (m, 2H),1.30 (m, 1H), 1.17 (m, 3H), 1.03 (m, 1H), 0.88 (d, 3H)

Melting point: 222-223° C.

Yield: 55%

Example 1722,6-Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide

C₃₂H₃₅F₂N₃O₅S Mw. 611.71

LC/MS purity: 98%, m/z 610 [M−H]⁻, 612 [M+H]⁺ Rt. 3.64 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.40 (d, 1H), 7.67 (m, 1H),7.51 (s, 1H), 7.36 (m, 1H), 7.25 (t, 2H), 7.05 (m, 3H), 6.16 (d, 1H),4.17 (t, 2H), 3.92 (s, 3H), 2.88 (m, 2H), 2.49 (m, 2H), 1.97 (m, 7H),1.58 (m, 2H), 1.33 (m, 1H), 1.16 (m, 2H), 0.88 (d, 3H)

Melting point: 191-193° C.

Yield: 44%

Example 1732,6-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₃H₃₅F₃N₃O₆S Mw. 627.71

LC/MS purity: 99%, m/z 628 [M−H]⁻, 626 [M+H]⁺ Rt. 3.36 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.37 (d, 1H), 7.62 (m, 1H), 7.46(s, 1H), 7.33 (s, 1H), 7.20 (t, 2H), 7.04 (d, 1H), 6.92 (s, 1H), 6.68(d, 1H), 6.15 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 3.60 (s, 3H), 3.32(m, 1H), 2.83 (m, 2H), 2.46 (m, 2H), 1.94 (m, 3H), 1.62 (m, 4H), 1.45(m, 1H), 0.84 (d, 3H)

Melting point: 98-101° C.

Yield: 47%

Example 174N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-2-trifluoromethoxy-benzenesulfonamide

C₃₃H₃₆F₃N₃O₆S Mw. 659.73

LC/MS purity: 98%, m/z 658[M−H]⁻, 660 [M+H]⁺ Rt. 4.18 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.40 (d, 1H), 7.98 (dd, 1H),7.76 (m, 1H), 7.54 (m, 2H), 7.50 (s, 1H), 7.36 (s, 1H), 7.09 (d, 1H),7.00 (m, 2H), 6.15 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.86 (m, 2H),2.46 (m, 2H), 2.00 (m, 3H), 1.93 (m, 4H), 1.58 (m, 2H), 1.33 (m, 1H),1.16 (m, 2H), 0.88 (d, 3H)

Melting point: 168-169° C.

Yield: 51%

Example 1752,5-Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide

C₃₂H₃₅Cl₂N₃O₅S Mw. 644.62

LC/MS purity: 100%, m/z 642 [M−H]⁻, 644 [M+H]⁺ Rt. 3.33 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.40 (d, 1H), 7.97 (d, 1H),7.69 (m, 2H), 7.50 (s, 1H), 7.36 (s, 1H), 7.07 (d, 1H), 7.01 (m, 2H),6.16 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.91 (m, 2H), 2.51 (m, 2H),2.01 (m, 7H), 1.60 (m, 2H), 1.35 (m, 1H), 1.15 (m, 2H), 0.88 (d, 3H)

Melting point: 187-188° C.

Yield: 48%

Example 1762,6-Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide

C₃₂H₃₅Cl₂N₃O₅S Mw. 644.62

LC/MS purity: 95%, m/z 642 [M−H]⁻, 644 [M+H]⁺ Rt. 4.00 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.7 (bs, 1H), 8.39 (d, 1H), 7.62 (m, 2H),7.54 (d, 1H), 7.49 (s, 1H), 7.35 (s, 1H), 7.11 (s, 1H), 7.03 (m, 2H),6.14 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.88 (m, 2H), 2.50 (m, 2H),1.99 (s, 3H), 1.96 (m, 4H), 1.58 (m, 2H), 1.34 (m, 1H), 1.16 (m, 2H),0.88 (d, 3H)

Melting point: 209-210° C.

Yield: 35%

Example 177N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,5-difluoro-benzenesulfonamide

C₂₇H₂₆F₃N₃O₅S Mw. 561.58

LC/MS purity: 99%, m/z 560 [M−H]⁻, 562 [M+H]⁺ Rt. 2.87 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.44 (d, 1H), 7.57 (m, 1H), 7.49(s, 1H), 7.42 (s, 2H), 7.38 (s, 1H), 7.17 (s, 1H), 7.00 (d, 1H), 6.85(d, 1H), 6.36 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H), 2.69 (t, 2H), 2.40(s, 6H), 2.03 (m, 2H)

Melting point: 108-110° C.

Yield: 64%

Example 178N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,6-difluoro-benzenesulfonamide

C₂₇H₂₆F₃N₃O₅S Mw. 561.58

LC/MS purity: 99%, m/z 560 [M−H]⁻, 562 [M+H]⁺ Rt. 2.77 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.44 (d, 1H), 7.56 (m, 1H),7.49 (s, 1H), 7.37 (s, 1H), 7.18 (m, 3H), 7.01 (dd, 1H), 6.85 (d, 1H),6.35 (d, 1H), 4.19 (t, 2H), 3.93 (s, 3H), 2.66 (t, 2H), 2.37 (s, 6H),2.02 (m, 2H)

Melting point: 125-127° C.

Yield: 53%

Example 179N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethoxy-benzenesulfonamide

C₂₈H₂₇F₄N₃O₆S Mw. 609.60

LC/MS purity: 99%, m/z 608 [M−H]⁻, 610 [M+H]⁺ Rt. 3.28 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 7.99 (d, 1H),7.69 (t, 1H), 7.51 (m, 3H), 7.37 (s, 1H), 7.21 (t, 1H), 7.04 (dd, 1H),6.87 (d, 1H), 6.35 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 2.58 (t, 2H),2.31 (s, 6H), 1.99 (m, 2H)

Melting point: 94-96° C.

Yield: 56%

Example 1802,5-Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-benzenesulfonamide

C₂₇H₂₆Cl₂FN₃O₅S Mw. 594.49

LC/MS purity: 99%, m/z 592 [M−H]⁻, 594 [M+H]⁺ Rt. 3.15 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.43 (d, 1H), 7.96 (s, 1H),7.56 (s, 2H), 7.49 (s, 1H), 7.37 (s, 1H), 7.13 (t, 1H), 6.93 (d, 1H),6.80 (d, 1H), 6.35 (d, 1H), 4.19 (t, 2H), 3.93 (s, 3H), 2.67 (t, 2H),2.38 (s, 6H), 2.03 (m, 2H)

Melting point: 150-152° C.

Yield: 62%

Example 1812,6-Dichloro-N-{-4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-benzenesulfonamide

C₂₇H₂₆Cl₂FN₃O₅S Mw. 594.49

LC/MS purity: 100%, m/z 592 [M−H]⁻, 594 [M+H]⁺ Rt. 1.23 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.43 (d, 1H), 7.46 (s, 4H),7.37 (s, 1H), 7.19 (t, 1H), 7.00 (dd, 1H), 6.84 (d, 1H), 6.34 (d, 1H),4.19 (t, 2H), 3.92 (s, 3H), 2.67 (t, 2H), 2.38 (s, 6H), 2.02 (m, 2H)

Melting point: 197-198° C.

Yield: 44%

Example 182 5-Chloro-thiophene-2-sulfonic acid{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}amide

C₂₅H₂₅ClFN₃O₅S₂ Mw. 566.07

LC/MS purity: 99%, m/z 564 [M−H]⁻, 566 [M+H]⁺ Rt. 2.89 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.45 (d, 1H), 7.51 (s, 1H),7.39 (s, 1H), 7.30 (d, 1H), 7.20 (t, 1H), 7.10 (d, 1H), 7.02 (dd, 1H),6.88 (d, 1H), 6.39 (d, 1H), 4.21 (t, 2H), 3.94 (s, 3H), 2.76 (t, 2H),2.45 (s, 6H), 2.05 (m, 2H)

Melting point: 130-132° C.

Yield: 45%

Example 183N-(5-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenylsulfamoyl}-4-methyl-thiazol-2-yl)-acetamide

C₂₇H₃₀FN₅O₆S₂ Mw. 603.69

LC/MS purity: 100%, m/z 602 [M−H], 604 [M+H]⁺ Rt. 2.56 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 12 (bs, 1H), 10.5 (bs, 1H), 8.44 (d, 1H),7.49 (s, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.09 (dd, 1H), 6.96 (d, 1H),6.36 (d, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 2.54 (t, 2H), 2.39 (s, 3H),2.26 (s, 6H), 2.15 (s, 3H), 1.98 (m, 2H)

Melting point: 164-166° C.

Yield: 42%

Example 1843-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenylsulfamoyl}-thiophene-2-carboxylicacid methyl ester

C₂₇H₂₈FN₃O₇S₂ Mw. 589.66

LC/MS purity: 96%, m/z 588 [M−H]⁻, 590 [M+H]⁺ Rt. 3.16 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.45 (d, 1H), 7.94 (d, 1H),7.48 (s, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 7.29 (t, 1H), 7.11 (dd, 1H),6.97 (d, 1H), 6.36 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 3.87 (s, 3H),2.47 (t, 2H), 2.24 (s, 6H), 1.98 (m, 2H)

Melting point: 80-82° C.

Yield: 39%

Example 185 Furan-2-sulfonic acid{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-amide

C₂₅H₂₆FN₃O₆S Mw. 515.56

LC/MS purity: 98%, m/z 514 [M−H]⁻, 516 [M+H]⁺ Rt. 2.62 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.45 (d, 1H), 7.84 (s, 1H),7.50 (s, 1H), 7.38 (s, 1H), 7.22 (t, 1H), 7.03 (m, 3H), 6.58 (s, 1H),6.38 (d, 1H), 4.19 (t, 2H), 3.93 (s, 3H), 2.60 (t, 2H), 2.33 (s, 6H),2.00 (m, 2H)

Melting point: 185-187° C.

Yield: 47%

Example 186

Thiophene-2-sulfonic acid{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-amide

C₂₅H₂₆FN₃O₅S₂ Mw. 531.62

LC/MS purity: 99%, m/z 530 [M−H]⁻, 532 [M+H]⁺ Rt. 2.82 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.46 (d, 1H), 7.85 (s, 1H),7.54 (s, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.30 (t, 1H), 7.11 (m, 2H),6.98 (d, 1H), 6.37 (d, 1H), 4.19 (t, 2H), 3.93 (s, 3H), 2.57 (t, 2H),2.30 (s, 6H), 1.99 (m, 2H)

Melting point: 186-188° C.

Yield: 36%

Example 1872,5-Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂F₃N₃O₅S Mw. 615.68

LC/MS purity: 97%, m/z 614 [M−H]⁻, 616 [M+H]⁺ Rt. 3.37 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 7.46 (m, 5H),7.27 (t, 1H), 6.95 (m, 2H), 6.27 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H),3.03 (m, 2H), 2.67 (t, 2H), 2.18 (m, 2H), 2.04 (m, 2H), 1.64 (m, 2H),1.40 (m, 1H), 1.20 (m, 2H), 0.90 (d, 3H)

Melting point: 186-188° C.

Yield: 54%

Example 1882,6-Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂F₃N₃O₅S Mw. 615.68

LC/MS purity: 98%, m/z 614 [M−H]⁻, 616 [M+H]⁺ Rt. 3.26 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.45 (d, 1H), 7.62 (m, 1H),7.46 (s, 1H), 7.40 (s, 1H), 7.31 (t, 1H), 7.16 (m, 2H), 6.97 (m, 2H),6.26 (d, 1H), 4.21 (t, 2H), 3.92 (s, 3H), 3.03 (m, 2H), 2.66 (t, 2H),2.18 (m, 2H), 2.04 (m, 2H), 1.64 (m, 2H), 1.41 (m, 1H), 1.20 (m, 2H),0.90 (d, 3H)

Melting point: 185-186° C.

Yield: 38%

Example 189N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₂H₃₃F₄N₃O₅S Mw. 647.69

LC/MS purity: 97%, m/z 646 [M−H]⁻, 648 [M+H]⁺ Rt. 3.63 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.45 (d, 1H), 8.04 (m, 1H),7.91 (m, 1H), 7.77 (m, 2H), 7.42 (s, 1H), 7.39 (s, 1H), 7.30 (t, 1H),6.94 (m, 2H), 6.28 (d, 1H), 4.20 (t, 2H), 3.91 (s, 3H), 2.98 (m, 2H),2.60 (t, 2H), 2.05 (m, 4H), 1.62 (m, 2H), 1.40 (m, 1H), 1.20 (m, 2H),0.89 (d, 3H)

Melting point: 175-177° C.

Yield: 44%

Example 190N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide

C₃₂H₃₃F₄N₃O₆S Mw. 663.69

LC/MS purity: 98%, m/z 662 [M−H]⁻, 664 [M+H]⁺ Rt. 3.85 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.46 (d, 1H), 7.88 (d, 1H),7.71 (t, 1H), 7.45 (m, 4H), 7.31 (t, 1H), 6.96 (m, 2H), 6.25 (d, 1H),4.20 (t, 2H), 3.91 (s, 3H), 2.95 (m, 2H), 2.57 (t, 2H), 2.02 (m, 4H),1.62 (m, 2H), 1.36 (m, 1H), 1.17 (m, 2H), 0.89 (d, 3H)

Melting point: 80-82° C.

Yield: 37%

Example 1912,5-Dichloro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂Cl₂FN₃O₅S Mw. 648.58

LC/MS purity: 95%, m/z 646 [M−H]⁻, 648 [M+H]⁺ Rt. 3.64 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.45 (d, 1H), 7.87 (d, 1H),7.61 (m, 2H), 7.46 (s, 1H), 7.40 (s, 1H), 7.26 (t, 1H), 6.93 (m, 2H),6.24 (d, 1H), 4.21 (t, 2H), 3.93 (s, 3H), 3.07 (m, 2H), 2.69 (t, 2H),2.21 (m, 2H), 2.05 (m, 2H), 1.66 (m, 2H), 1.43 (m, 1H), 1.23 (m, 2H),0.90 (d, 3H)

Melting point: 127-130° C.

Yield: 52%

Example 1922,6-Dichloro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂Cl₂FN₃O₅S Mw. 648.58

LC/MS purity: 97%, m/z 646 [M−H]⁻, 648 [M+H]⁺ Rt. 3.56 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.43 (d, 1H), 7.45 (m, 5H),7.30 (t, 1H), 6.93 (m, 2H), 6.22 (d, 1H), 4.21 (t, 2H), 3.93 (s, 3H),3.00 (m, 2H), 2.64 (m, 2H), 2.10 (m, 4H), 1.64 (m, 2H), 1.39 (m, 1H),1.19 (m, 2H), 0.90 (d, 3H)

Melting point: 116-118° C.

Yield: 46%

Example 193N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide

C₃₁H₃₂ClF₂N₃O₅S Mw. 632.13

LC/MS purity: 97%, m/z 630 [M−H]⁻, 632 [M+H]⁺ Rt. 3.24 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.1 (bs, 1H), 8.36 (d, 1H), 7.44 (s, 1H),7.38 (t, 1H), 7.25 (m, 4H), 7.05 (d, 1H), 6.43 (dd, 1H), 6.27 (d, 1H),4.22 (t, 2H), 3.92 (s, 3H), 3.19 (m, 2H), 2.89 (m, 2H), 2.56 (m, 1H),2.11 (m, 2H), 1.72 (m, 2H), 1.36 (m, 1H), 1.28 (m, 3H), 0.92 (d, 3H)

Melting point: 206-208° C.

Yield: 11%

Example 194N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide

C₃₁H₃₂ClF₂N₃O₅S Mw. 632.13

LC/MS purity: 98%, m/z 630 [M−H]⁻, 632 [M+H]⁺ Rt. 3.23 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.1 (bs, 1H), 8.35 (d, 1H), 7.44 (s, 1H),7.35 (m, 2H), 7.24 (d, 1H), 7.06 (d, 1H), 6.91 (t, 2H), 6.39 (dd, 1H),6.23 (d, 1H), 4.23 (t, 2H), 3.92 (s, 3H), 3.17 (m, 2H), 2.97 (m, 2H),2.57 (m, 1H), 2.14 (m, 2H), 1.75 (m, 2H), 1.53 (m, 1H), 1.26 (m, 3H),0.93 (d, 3H)

Melting point: 222-226° C.

Yield: 14%

Example 195N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₂H₃₃ClF₃N₃O₅S Mw. 664.14

LC/MS purity: 98%, m/z 662 [M−H]⁻, 664 [M+H]⁺ Rt. 3.43 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.15 (bs, 1H), 8.31 (d, 1H), 7.95 (d, 1H),7.72 (d, 1H), 7.57 (m, 2H), 7.38 (s, 1H), 7.36 (s, 1H), 7.27 (d, 1H),6.89 (d, 1H), 6.40 (d, 1H), 6.19 (d, 1H), 4.22 (t, 2H), 3.89 (s, 3H),3.31 (m, 2H), 3.01 (m, 2H), 2.61 (m, 1H), 2.15 (m, 2H), 1.75 (m, 2H),1.54 (m, 1H), 1.29 (m, 3H), 0.93 (d, 3H)

Melting point: 179-181° C.

Yield: 12%

Example 196N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide

C₃₂H₃₃ClF₃N₃O₆S Mw. 680.14

LC/MS purity: 98%, m/z 678 [M−H]⁻, 680 [M+H]⁺ Rt. 3.58 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.1 (bs, 1H), 8.35 (d, 1H), 7.74 (d, 1H),7.50 (t, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.29 (m, 3H), 7.01 (d, 1H),6.43 (d, 1H), 6.27 (d, 1H), 4.23 (t, 2H), 3.90 (s, 3H), 3.29 (m, 2H),3.02 (m, 2H), 2.68 (m, 1H), 2.16 (m, 2H), 1.77 (m, 2H), 1.56 (m, 1H),1.29 (m, 3H), 0.93 (d, 3H)

Melting point: 123-126° C.

Yield: 9

Example 1972,5-Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂Cl₃N₃O₅S Mw. 665.04

LC/MS purity: 97%, m/z 662 [M−H]⁻, 664 [M+H]⁺ Rt. 3.49 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9.1 (bs, 1H), 8.37 (d, 1H), 7.75 (d, 1H),7.40 (m, 4H), 7.27 (d, 1H), 6.98 (d, 1H), 6.40 (dd, 1H), 6.24 (d, 1H),4.22 (t, 2H), 3.92 (s, 3H), 3.31 (m, 2H), 3.17 (m, 2H), 2.98 (m, 1H),2.11 (m, 2H), 1.73 (m, 2H), 1.55 (m, 1H), 1.26 (m, 3H), 0.92 (d, 3H)

Melting point: 223-224° C.

Yield: 12%

Example 1982,6-Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₁H₃₂Cl₃N₃O₅S Mw. 665.04

LC/MS purity: 98%, m/z 662 [M−H]⁻, 664 [M+H]⁺ Rt. 3.38 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 9 (bs, 1H), 8.32 (d, 1H), 7.42 (s, 1H), 7.38(s, 1H), 7.26 (m, 4H), 6.94 (d, 1H), 6.37 (dd, 1H), 6.17 (d, 1H), 4.23(t, 2H), 3.91 (s, 3H), 3.28 (m, 2H), 2.96 (m, 2H), 2.54 (m, 1H), 2.14(m, 2H), 1.75 (m, 2H), 1.53 (m, 1H), 1.30 (m, 3H), 0.93 (d, 3H)

Melting point: 206-208° C.

Yield: 9%

Example 1992,5-Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-benzenesulfonamide

C₂₂H₁₅F₃N₂O₄S Mw. 460.43

LC/MS purity: 98%, m/z 459 [M−H]⁻, 461 [M+H]⁺ Rt. 3.42 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.58 (d, 1H), 8.17 (d, 1H), 7.64(m, 1H), 7.48 (m, 1H), 7.40 (s, 1H), 7.39 (m, 1H), 7.26 (m, 2H), 7.06(dd, 1H), 6.92 (d, 1H), 6.37 (d, 1H), 3.93 (s, 3H)

Melting point: 249-250° C.

Yield: 81%

Example 2002,6-Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]benzenesulfonamide

C₂₂H₁₅F₃N₂O₄S Mw. 460.43

LC/MS purity: 98%, m/z 459 [M−H]⁻, 461 [M+H]⁺ Rt. 3.27 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.3 (bs, 1H), 8.59 (d, 1H), 8.17 (d, 1H),7.70 (m, 1H), 7.4-7.25 (m, 6H), 7.14 (dd, 1H), 7.01 (d, 1H), 3.93 (s,3H)

Melting point: 227-228° C.

Yield: 69%

Example 201N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethyl-benzenesulfonamide

C₂₃H₁₆F₄N₂O₄S Mw. 492.45

LC/MS purity: 98%, m/z 491 [M−H]⁻, 493 [M+H]⁺ Rt. 3.75 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.59 (d, 1H), 8.18 (s, 1H), 8.15(s, 1H), 8.02 (d, 1H), 7.89 (m, 2H), 7.40 (s, 1H), 7.36 (d, 1H), 7.29(dd, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 6.37 (d, 1H), 3.93 (s, 3H)

Melting point: 168-169° C.

Yield: 75%

Example 202N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethoxy-benzensulfonamide

C₂₃H₁₆F₄N₂O₅S Mw. 508.45

LC/MS purity: 99%, m/z 507 [M−H]⁻, 509 [M+H]⁺ Rt. 3.97 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.59 (d, 1H), 8.18 (s, 1H), 8.05(d, 1H), 7.81 (t, 1H), 7.59 (m, 2H), 7.40 (s, 1H), 7.36 (d, 1H), 7.29(dd, 1H), 7.15 (d, 1H), 7.00 (d, 1H), 6.34 (d, 1H), 3.93 (s, 3H)

Melting point: 175-176° C.

Yield: 69%

Example 2032,5-Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-benzenesulfonamide

C₂₂H₁₅Cl₂FN₂O₄S Mw. 493.34

LC/MS purity: 98%, m/z 491 [M−H]⁻, 493 [M+H]⁺ Rt. 3.78 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1H), 8.58 (d, 1H), 8.17 (d, 1H),8.05 (d, 1H), 7.74 (m, 2H), 7.39 (d, 1H), 7.35 (t, 1H), 7.28 (dd, 1H),7.16 (dd, 1H), 7.01 (d, 1H), 6.36 (d, 1H), 3.93 (s, 3H)

Melting point: 253-255° C.

Yield: 70%

Example 2042,6-Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]benzenesulfonamide

C₂₂H₁₅Cl₂FN₂O₄S Mw. 493.34

LC/MS purity: 99%, m/z 491 [M−H]⁻, 493 [M+H]⁺ Rt. 3.69 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1H), 8.58 (d, 1H), 8.17 (d, 1H),7.62 (m, 2H), 7.54 (m, 1H), 7.40 (d, 1H), 7.34 (t, 1H), 7.27 (dd, 1H),7.00 (dd, 1H), 6.96 (d, 1H), 6.35 (d, 1H), 3.93 (s, 3H)

Melting point: 219-221° C.

Yield: 67%

Example 205

Naphthalene-2-sulfonic acid[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-amide

C₂₆H₁₉FN₂O₄S Mw. 474.51

LC/MS purity: 99%, m/z 473 [M−H]⁻, 475 [M+H]⁺ Rt. 4.20 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.53 (d, 1H), 8.49 (s, 1H),8.19 (m, 3H), 8.03 (d, 1H), 7.82 (dd, 1H), 7.69 (m, 2H), 7.38 (d, 1H),7.27 (m, 2H), 7.16 (dd, 1H), 6.99 (t, 1H), 6.28 (d, 1H), 3.92 (s, 3H)

Melting point: 220-222° C.

Yield: 74%

Example 206

Cyclopropanesulfonic acid[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-amide

C₁₉H₁₇FN₂O₄S Mw. 388.42

LC/MS purity: 98%, m/z 387 [M−H]⁻, 389 [M+H]⁺ Rt. 3.64 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.62 (dd, 1H), 8.22 (d, 1H),7.48 (d, 1H), 7.43 (s, 1H), 7.29 (m, 2H), 7.18 (d, 1H), 6.48 (d, 1H),3.94 (s, 3H), 2.76 (m, 1H), 0.99 (m, 4H)

Melting point: 194-196° C.

Yield: 75%

Example 2072,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide

C₃₂H₃₅F₂N₃O₆S Mw. 627.71

LC/MS purity: 98%, m/z 626 [M−H]⁻, 628 [M+H]⁺ Rt. 3.50 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.37 (d, 1H), 7.63 (m, 1H),7.51 (m, 2H), 7.46 (s, 1H), 7.34 (s, 1H), 7.07 (d, 1H), 6.90 (s, 1H),6.70 (d, 1H), 6.16 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 3.61 (s, 3H),3.34 (m, 1H), 2.84 (m, 2H), 2.46 (m, 2H), 1.95 (m, 3H), 1.63 (m, 4H),1.48 (m, 1H), 0.84 (d, 3H)

Melting point: 170-172° C.

Yield: 58%

Example 208N-(3-Methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₃H₃₆F₃N₃O₆S Mw. 659.73

LC/MS purity: 98%, m/z 658 [M−H]⁻, 660 [M+H]⁺ Rt. 3.86 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.38 (d, 1H), 8.15 (d, 1H),7.97 (d, 1H), 7.83 (m, 2H), 7.45 (s, 1H), 7.34 (s, 1H), 7.07 (d, 1H),6.91 (d, 1H), 6.67 (dd, 1H), 6.17 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H),3.60 (s, 3H), 3.32 (m, 1H), 2.81 (m, 2H), 2.46 (m, 2H), 1.96 (m, 2H),1.88 (m, 1H), 1.60 (m, 4H), 1.46 (m, 1H), 0.84 (d, 3H)

Melting point: 216-218° C.

Yield: 53° A

Example 209N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide

C₃₁H₃₁Cl₂F₂N₃O₅S Mw. 666.58

LC/MS purity: 96%, m/z 664 [M−H]⁻, 666 [M+H]⁺ Rt. 3.34 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.43 (d, 1H), 7.53 (s, 1H),7.45 (m, 1H), 7.41 (s, 1H), 7.07 (m, 2H), 7.02 (m, 2H), 6.26 (d, 1H),4.23 (t, 2H), 3.94 (s, 3H), 3.28 (m, 2H), 2.95 (m, 2H), 2.52 (m, 1H),2.13 (m, 2H), 1.74 (m, 2H), 1.53 (m, 1H), 1.29 (m, 3H), 0.92 (d, 3H)

Melting point: 146-151° C.

Yield: 7%

Example 210N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₂H₃₂Cl₂F₃N₃O₅S Mw. 698.59

LC/MS purity: 98%, m/z 696 [M−H]⁻, 698 [M+H]⁺ Rt. 3.59 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.43 (d, 1H), 8.11 (d, 1H),7.82 (d, 1H), 7.69 (m, 2H), 7.52 (s, 1H), 7.41 (s, 1H), 6.96 (s, 2H),6.25 (d, 1H), 4.22 (t, 2H), 3.93 (s, 3H), 3.28 (m, 2H), 2.69 (m, 2H),2.56 (m, 1H), 2.27 (m, 2H), 1.72 (m, 2H), 1.50 (m, 1H), 1.32 (m, 3H),0.92 (d, 3H)

Melting point: 148-151° C.

Yield: 22%

Example 211 Acetic acid4-{4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-butylester

C₂₈H₂₅F₃N₂O₇S Mw. 590.58

LC/MS purity: 98%, m/z 589 [M−H]⁻, 591 [M+H]⁺ Rt. 3.57 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.11 (s, 1H), 8.45 (d, 1H), 7.71-7.35 (m,6H), 7.18 (d, 1H), 7.05 (d, 1H), 6.36 (d, 1H), 4.17 (bs, 2H), 4.10 (bs,2H), 3.92 (s, 3H), 2.01 (s, 3H), 1.84 (bs, 2H), 1.80 bs, 2H)

Melting point: 165-167° C.

Yield: 65%

Example 212

Acetic acid4-{-4-[2-fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-butylester

C₂₉H₂₆F₄N₂O₇S Mw. 622.60

LC/MS purity: 98%, m/z 621 [M−H]⁻, 623 [M+H]⁺ Rt. 3.86 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11.03 (s, 1H), 8.45 (d, 1H), 8.16 (d, 1H),8.04 (d, 1H), 7.80 (m, 2H), 7.47 (s, 1H), 7.39 (s, 1H), 7.37 (t, 1H),7.16 (d, 1H), 7.03 (d, 1H), 6.36 (d, 1H), 4.17 (t, 2H), 4.10 (t, 2H),3.91 (s, 3H), 2.01 (s, 3H), 1.82 (m, 4H)

Melting point: 143-145° C.

Yield: 74%

Example 213N-{2-Fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethyl-benzenesulfonamide

C₃₀H₂₉F₄N₃O₅S Mw. 619.64

LC/MS purity: 99%, m/z 618 [M−H]⁻, 620 [M+H]⁺ Rt. 2.71 min. (Method A)

¹H NMR (300 MHz, DMSO-d6): 11.03 (s, 1H), 8.45 (d, 1H), 8.16 (d, 1H),8.04 (d, 1H), 7.80 (m, 2H), 7.47 (s, 1H), 7.39 (s, 1H), 7.37 (t, 1H),7.16 (d, 1H), 7.03 (d, 1H), 6.36 (d, 1H), 4.17 (t, 2H), 4.10 (t, 2H),3.91 (s, 3H), 2.01 (s, 3H), 1.82 (m, 4H)

Melting point: 152-156° C.

Yield: 62%

Example 214N-{3-Fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-2-trifluoromethyl-benzenesulfonamide

C₃₁H₃₁F₄N₃O₆S Mw. 649.67

LC/MS purity: 97%, m/z 648 [M−H]⁻, 650 [M+H]⁺ Rt. 3.50 min. (Method B)

¹H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.44 (d, 1H), 8.16 (d, 1H), 8.01(d, 1H), 7.90 (m, 2H), 7.46 (s, 1H), 7.38 (s, 1H), 7.33 (t, 1H), 7.13(d, 1H), 6.98 (d, 1H), 6.35 (d, 1H), 4.16 (t, 2H), 3.91 (s, 3H), 3.57(m, 4H), 2.38 (m, 6H), 1.82 (m, 2H), 1.64 (m, 2H)

Melting point: 102-104° C.

Yield: 23%

Example 215N-(2-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide

C₃₂H₃₃F₄N₃O₅S Mw. 647.69

LC/MS purity: 95%, m/z 646 [M−H]⁻, m/z 648 [M−H]⁺ Rt. 3.60 min. (MethodB)

¹H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.44 (d, 1H), 8.07 (d, 1H),7.81 (d, 1H), 7.65 (m, 2H), 7.43 (s, 1H), 7.35 (s, 1H), 7.14 (t, 1H),6.96 (d, 1H), 6.76 (d, 1H), 6.43 (d, 1H), 4.17 (t, 2H), 3.90 (s, 3H),2.85 (m, 2H), 2.42 (m, 2H), 1.98 (m, 2H), 1.82 (m, 1H), 1.61 (m, 4H),1.51 (m, 1H), 1.03 (m, 1H), 0.84 (d, 3H)

Melting point: 125-126° C.

Yield: 35%

Assay Example A:

AXL Cellular Tyrosine Kinase Assay

Establishment of Wild Type AXL (wtAXL) Receptor TyrosineKinase-Overexpressing Stable Cell Line NIH-3T3-AXL (Clone 22)

WtAXL cDNA was cloned into vector pLXSN(ESK) and transfected intoPhoenix E packaging cells. The viral supernatant was collected and usedto infect target cells NIH3T3 N7. Monoclonal NIH3T3-AXL cell linesstably expressing wtAXL were generated by selecting retrovirallyinfected cells in medium containing puromycin (2 μg/ml) and subsequentclonal separation. NIH-3T3-AXL (clone 22) cells were used for furtherexperiment because AXL was highly expressed and constitutivelyphosphorylated in these cells. In addition, these cells demonstratedaggressive behaviors on matrigel matrix (Matrigel™ Matrix, BDBiosciences, Bedford, Mass., USA). Moreover, the inhibitory effects ofcompounds on AXL phosphorylation discovered by using NIH-3T3 AXL (clone22) system have been confirmed in human breast cancer cells endogenouslyexpressing AXL in our previous study (Zhang Y X, et al. AXL is apotential target for therapeutic intervention in breast cancerprogression. Cancer Res. 2008; 68:1905-15).

Determination of the morphology of cells grown on matrigel matrix wascarried out as described previously, with some modifications (Thompson EW, et al. Association of increased basement membrane invasiveness withabsence of estrogen receptor and expression of vimentin in human breastcancer cell lines. J Cell Physiol 1992; 150:534-44). Briefly, in a96-well flat-bottomed plate, 10000 cells/100 μl cell suspensions wasplated on the surface of precoated matrigel (3 mg/ml). Colony outgrowthwas visualized with a Zeiss Axiovert S100 microscope (Carl Zeiss UK,Welwyn Garden City, UK).

NIH-3T3-AXL Cellular Kinase Assay

NIH-3T3-AXL (Clone 22) cells were seeded onto 6-well plates (1.5×10⁵cells/well) in 1.5 ml DMEM+10% heat inactivated FBS (GIBCO-InvitrogenGmbH, Karlsruhe, Germany) and cultured overnight, followed by serumdepletion in DMEM without FBS for 24 h. Serial dilutions of compoundswere added, and the cells were further incubated for 1 h. Cells werewashed with PBS and lysed on ice in 500 μl lysis buffer (50 mM HEPES (pH7.5), 150 mM NaCl, 1 mM EGTA, 10% Glycerol, 1% Triton X-100, 100 mM NaF,10 mM Na₄P₂O₇.10 H₂O, 1 mM Na₃VO₄, 1 mM phenylmethylsulfonyl fluoride,and 10 mg/ml aprotinin) for 15 min. The cell lysate were used forphosphotyrosine AXL enzyme-linked immunosorbant assay (pY-AXL-ELISA).96-well Nunc MicroWell™ plates (Fischer Scientific GmbH, Schwerte,Germany) were coated over night with homemade anti-Axl capture antibody2 μg/ml (clone 259/2, IgG1 isotype) in PBS (100 μl/well). Subsequently96-well plates were blocked with PBS-0.05% Tween®20+10% FBS for 4 h at37° C. Plates were washed 5 times with PBS-0.05% Tween®20 and 95 μl oflysate was transferred per well for incubation overnight at 4° C. Plateswere washed 5 times with PBS-0.05% Tween®20 (Sigma, Steinheim, Germany).For detection of phosphorylated tyrosine we used homemade biotynilated4G10-antibody (0.5 μg/ml) in PBS-0.05% Tween®20+10% FBS (100 μl/well)and incubated the 96-well plate for 2 h at room temperature. Theanti-phosphotyrosine mouse monoclonal antibody 4G10 was biotynilatedwith Sulfo-NHS®-Biotin according to the suppliers protocol (Pierce,Rockford, Ill., USA) and purified by Mirco Bio-Spin 6 ChromatograpyColumns (B10 RAD Laboratories, Inc., Hercules, Calif., USA) using PBS asdiluent. Plates were washed 5 times with PBS-0.05% Tween®20. For bidingto biotin Alkaline Phosphatase Conjugated Strepavidin SA110 (Millipore,Billerica, Mass., USA) (1:4000) was used in PBS-0.05% Tween20+10% FBS(100 μl/well) and incubated for 30 min at room temperature. Plates werewashed 5 times with PBS-0.05% Tween20. For fluorimetric detection ofalkaline phosphatase AttoPhos Substrate Set (Roche diagnostics GmbH,Mannheim, Germany) was used (100 μl/well). The fluorimetric signal wasquantified after 90 min at 430/560 nm wavelength using a TECAN UltraEvolution plate reader (Tecan Deutschland GmbH, Crailsheim, Germany).

Table Ia below shows for the cell line NIH-3T3-Axl in column 2 thehalf-maximal inhibition concentration (IC₅₀) values of representativecompounds according to general formula (I) (+=3 μM>IC₅₀>500 nM &++=IC₅₀≦500 nM) obtained according to the disclosure above of AssayExample A.

TABLE Ia Inhibitory effect of the compounds of the present invention onthe NIH-3T3-axl cell line [0]pY-Axl-ELISA on NIH-3T3-Axl cells ExampleNo (cellular IC50 [nM] 4 ++ 5 ++ 6 ++ 7 ++ 8 ++ 9 ++ 10 ++ 11 ++ 12 ++34 ++ 35 ++ 36 ++ 37 ++ 38 ++ 40 ++ 43 ++ 44 ++ 45 ++ 46 ++ 47 ++ 48 ++49 ++ 50 ++ 51 ++ 52 ++ 53 ++ 54 ++ 55 ++ 56 ++ 57 ++ 58 ++ 59 ++ 62 ++63 ++ 64 ++ 65 ++ 66 ++ 67 ++ 76 ++ 77 ++ 78 ++ 81 ++ 82 ++ 87 ++ 89 ++99 ++ 100 ++ 104 ++ 106 ++ 108 ++ 109 ++ 110 ++ 111 ++ 112 ++ 113 ++ 114++ 115 ++ 116 ++ 117 ++ 118 ++ 119 ++ 120 ++ 121 ++ 124 ++ 127 + 128 +134 + 136 + 144 ++ 145 ++ 146 ++ 147 + 148 + 151 ++ 152 ++ 153 ++ 154 ++155 ++ 156 ++ 157 ++ 158 ++ 171 + 172 + 173 + 174 + 175 + 176 + 177 ++178 ++ 179 ++ 180 ++ 181 ++ 182 ++ 184 ++ 185 + 186 ++ 191 + 193 + 194 +197 + 198 + 199 + 201 + 202 + 207 + 208 ++ 209 ++ 210 ++ 211 ++ 212 ++

Table Ib below shows the inhibitory effect of some compounds of thepresent invention on the cell line HS578T. In column 2 the experimentaldata of the “Matrigel outgrowth assay/branching assay” (+=25μM>IC₅₀>10.0 μM & ++=IC₅₀10.0 μM) as disclosed below under Assay ExampleE are shown and in column 3 the experimental data of the “Cell vitalityassay (ATP assay)” (+=50 μM>IC₅₀>12.5 μM & ++=IC₅₀ 12.5 μM) as disclosedbelow in section Assay Example B and in column 4 the experimental dataof the “Wound healing migration assay” (+=50 μM>IC₅₀>12.5 μM &++=IC₅₀≦12.5 μM) as outlined under Assay Example D are provided.

TABLE Ib Inhibitory effect of the compounds of the present invention onthe HS578T cell line Total branching inhibition in IC50 ATP- IC50 WoundExample Matrigel Assay HS578T healing No HS578T [μM] after 72 h [μM]Assay HS578T [μM] 1 ++ ++ ++ 2 3 4 ++ ++ ++ 5 + ++ + 6 ++ ++ ++ 7 + ++++ 8 ++ + ++ 9 + ++ + 10 ++ + ++ 11 + ++ ++ 12 ++ ++ ++ 13 14 15 ++ 1617 ++ 18 ++ 19 20 21 ++ 22 23 24 25 ++ 26 ++ 27 ++ 28 + 29 ++ 30 31 32++ 33 ++ 34 ++ ++ ++ 35 ++ ++ − 36 + ++ + 37 + ++ + 38 ++ + ++ 39 40 ++++ ++ 41 ++ 42 43 ++ ++ ++ 44 ++ ++ ++ 45 ++ ++ ++ 46 ++ ++ ++ 47 ++ ++++ 48 + ++ ++ 49 + ++ ++ 50 ++ ++ ++ 51 ++ ++ ++ 52 ++ ++ ++ 53 + ++ ++54 + ++ ++ 55 ++ + ++ 56 + + ++ 57 ++ ++ ++ 58 ++ ++ ++ 59 ++ ++ ++ 6061 62 + ++ + 63 ++ ++ ++ 64 + ++ ++ 65 + ++ ++ 66 + ++ ++ 67 ++ ++ ++ 6869 70 ++ 71 72 ++ 73 74 75 ++ 76 + ++ + 77 ++ ++ ++ 78 ++ ++ ++ 79 80 81++ ++ + 82 ++ ++ + 83 ++ 84 ++ 85 ++ 86 ++ 87 ++ + ++ 88 + 89 ++ ++ ++90 91 92 + ++ + 93 ++ 94 95 ++ 96 97 98 99 ++ ++ ++ 100 ++ ++ ++ 101 +102 + ++ ++ 104 + ++ ++ 106 + ++ + 108 + ++ + 109 + ++ + 110 ++ ++ ++111 ++ ++ ++ 112 ++ ++ ++ 113 ++ ++ ++ 114 + ++ + 115 ++ ++ ++ 116 + ++++ 117 + ++ ++ 119 ++ ++ ++ 120 + + + 121 + + + 124 ++ ++ ++ 125 + ++ ++126 + ++ ++ 127 ++ ++ ++ 128 ++ ++ ++ 129 ++ ++ ++ 130 ++ ++ + 131 +++ + 132 + + + 133 ++ ++ ++ 134 ++ ++ ++ 135 + + + 136 ++ ++ ++137 + + + 138 + + + 139 + + + 140 + + + 141 + + + 142 + + + 143 ++ ++ ++144 + ++ ++ 145 + ++ ++ 146 + ++ ++ 147 ++ ++ ++ 148 + ++ + 149 + + +150 + ++ + 151 ++ ++ ++ 152 ++ ++ ++ 153 + ++ ++ 154 + ++ ++ 155 + ++ ++156 + ++ ++ 157 + ++ ++ 158 + ++ ++ 159 + ++ + 160 + ++ ++ 161 + ++ +162 + ++ + 163 + ++ + 164 + ++ + 165 + ++ + 166 + ++ + 167 + + +168 + + + 169 + + + 170 + + + 171 + + + 172 ++ ++ ++ 173 + ++ + 174 ++++ ++ 175 ++ ++ ++ 176 ++ ++ ++ 177 ++ ++ ++ 178 ++ ++ + 179 + ++ ++ 180++ ++ ++ 181 ++ ++ ++ 182 + ++ ++ 183 + + + 184 + ++ ++ 185 + ++ + 186 +++ ++ 187 ++ ++ ++ 188 ++ ++ ++ 189 + + + 190 + + + 191 + ++ ++ 192 +++ + 193 + + ++ 194 + + + 195 + + + 196 + + + 197 + + + 198 + + +199 + + + 200 + + + 201 + + + 202 + + + 203 + ++ ++ 204 + + + 205 + + +206 + + + 207 + ++ ++ 208 + ++ + 209 ++ ++ ++ 210 ++ ++ ++ 211 + ++ ++212 + + +Cell Lines Used for Experiments:

Cell line Source Description Hs578T ECACC Mammary glad, adenocarcinomaMDA-MB231 ATCC no. HTB-26 Mammary glad, adenocarcinoma MCF10A ATCC no.CRL-10317 Mammary gland; breast MDA-MB435s ATCC no. HTB-129 Mammaryglad, adenocarcinoma SF126 M. Rosenblum Brain, glioblastoma SF763 SUGENBrain, glioblastoma U118 SUGEN Brain, glioblastoma U138 SUGEN Brain,glioblastoma U373 SUGEN Brain, glioblastoma A172 CRL-1620 Brain,glioblastoma A549 ATCC no. CCL-185 Lung, carcinoma NCI-H460 ATCC no.HTB-177 Lung, carcinoma NCI-H1299 ATCC no. CRL-5803 Lung, carcinomaC8161 B. Gillies Skin, melanoma SK-MEL-28 ATCC no. HTB-72 Skin, melanomaMIA PaCa-2 ATCC no. CRL-1420 Pancreas, carcinoma ASPC-1 ATCC no.CRL-1682 Pancreas, adenocarcinoma Panc-1 ATCC no. CRL-1469 Pancreas,epithelioid carcinoma 786-0 ATCC no. CRL-1932 Kidney, renal celladenocarcinoma DU145 ATCC no. HTB-81 Prostate, carcinoma PC3 ATCC no.CRL-1435 Prostate, adenocarcinoma HT29 ATCC no. HTB-38 Colon, colorectaladenocarcinomaAssay Example B: Cell Vitality Assay

The CellTiter-Glo® Luminescent Cell Viability Assay (PromegaCorporation. Madison, Wis., USA) is method a determining the number ofviable cells in culture based on quantification of the ATP being presentwhich is an indicator of metabolically active cells was used accordingto manufacturers protocol, In detail the assay was performed in a 96well format were 1000 cells/well were incubated with indicated compoundat concentration of 12.5 μM, 6.25 μM, 3.125 μM, 1.56 μM, 0.78 μM, 0.39μM, 0.195 μM as well as DMSO control for 72 h in 100 μl cell culturemedium. IC50 values were calculated as 50% of ATP amount compared toDMSO control.

Protocol for the CellTiter-Glo® Luminescent Cell Viability Assay

-   -   1. Prepare opaque-walled multiwell plates with mammalian cells        in culture medium, 100 μl per well for 96-well plates    -   2. Prepare control wells containing medium without cells to        obtain a value for background luminescence.    -   3. Add the compound to be tested to experimental wells, and        incubate according to culture protocol.    -   4. Equilibrate the plate and its contents at room temperature        for approximately 30 minutes.    -   5. Add a volume of CellTiter-Glo® Reagent (Promega Corporation.        Madison, Wis.) equal to the volume of cell culture medium        present in each well.    -   6. Mix contents for 2 minutes on an orbital shaker to induce        cell lysis.    -   7. Allow the plate to incubate at room temperature for 10        minutes to stabilize luminescent signal.    -   8. Record luminescence on Microplate Luminometer LB96V (Berthold        Technologies, Bad Wildbad, Germany). An integration time of 0.1        and 1 second per well

Table IIa below shows the IC₅₀ values of representative compoundsaccording to general formula (I) (+=50 μM>IC₅₀>12.5 μM & ++=IC₅₀≦12.5μM).

Example IC50 ATP-Assay after 72 h/[μM] No SF763 A172 SF126 U118 U138Hs578T MDA-MB231 C8161 1 ++ ++ ++ ++ ++ + + + 4 ++ ++ ++ 6 ++ ++ ++ 7++ + + + ++ ++ ++ ++ 8 ++ ++ ++ ++ ++ + − ++ 10 ++ ++ ++ ++ ++ + ++ ++11 + + + 12 ++ ++ ++ 14 ++ ++ + + − ++ ++ 21 + + + − − + + 25 ++ ++ ++++ ++ ++ ++ 29 + ++ ++ ++ + ++ ++ 32 ++ ++ ++ ++ ++ ++ ++ 33 ++ ++ ++ ++++ ++ ++ 38 ++ ++ ++ ++ ++ + ++ ++ 40 ++ ++ + 41 ++ + ++ ++ ++ ++ ++ 45++ ++ ++ 47 ++ ++ ++ ++ ++ ++ + + 49 ++ ++ ++ 51 ++ ++ ++ 54 ++ + ++55 + ++ + + + ++ ++ 56 ++ ++ + ++ + + ++ 59 ++ + + ++ ++ ++ ++ 63 ++ +++ + ++ ++ ++ 66 ++ ++ ++ 70 + ++ ++ ++ + + + 72 + + + + + + + 77 ++++ + ++ ++ ++ + ++ 78 ++ ++ ++ 87 ++ ++ ++ ++ ++ + + ++ 88 + + ++ + ++++ ++ 93 + ++ ++ + ++ + ++ 95 ++ ++ ++ ++ + ++ + 99 ++ ++ ++ ++ ++ ++++ + 100 ++ ++ ++ 104 + + + 110 ++ ++ ++ 112 ++ ++ ++ 119 ++ ++ ++ 151++ ++ ++ 155 ++ ++ ++ 156 ++ ++ ++ 157 ++ ++ ++ 158 ++ ++ ++ 177 ++ ++++ 178 ++ ++ ++ 179 ++ ++ ++ 181 ++ ++ ++ 184 ++ ++ ++ 209 ++ ++ ++ 210++ ++ ++Table IIb below shows the IC₅₀ values of representative compoundsaccording to general formula (I) (+=50 μM>IC₅₀>12.5 μM & ++=IC₅₀≦12.5μM).

Example No MCF10A MiaPaca-2 Aspc-1 Panc-1 DU145 PC3 786-0 SF126 24 ++ ++++ + ++ + ++ ++ 12 ++ ++ + ++ ++ ++ ++ 1 ++ ++ + ++ ++ + ++ 66 ++ ++ ++++ ++ ++ ++

Table IIc below shows the IC₅₀ values of representative compoundsaccording to general formula (I) (+=50 μM>IC₅₀>12.5 μM & ++=IC₅₀>12.5μM).

MDA- MDA- Example No U118 U373 A549 H460 HT29 MB435s MB231 24 + ++ ++ ++++ ++ ++ 12 ++ ++ ++ ++ ++ ++ ++ 1 ++ ++ ++ ++ ++ ++ ++ 66 ++ ++ ++ ++++ ++ ++Assay Example C: Apoptosis Assay

The Cellomics BioApplication (Thermo Fischer Cellomics Products,Pittsburgh, Pa.) is an automated image analysis algorithm that providesdetailed analysis of phenotypes related to apoptosis. As one of the mostprominent characteristics of apoptotics cell a nucleus condensationtakes place. This can be measured fluorescence signal intensity using aCCD camera on fully automated microscope system. The Cellomics system isable to quantify the fluorescence intensity per single nucleus andcalculates the variation of signal intensity in each cell population.Healthy cell have a low variation of signal intensity in contrast toapoptotic cell with condensed nucleus exhibiting a high variation ofsignal intensity. Additionally the number of detected cell decreasesnormally in apoptotic cell populations. In detail 5000 cell per 96 wellwere labeled with DNA intercalating dye (Hoechst 33342, Sigma,Steinheim, Germany) to visualize the nucleus in a fluorescencemicroscope under live conditions. The apoptosis assay was performed 24 hand 48 h after addition of compound at concentrations 12.5 μM, 6.25 μM,3.125 μM, 1.56 μM, 0.78 μM, 0.39 μM as well as DMSO control for 48 h.

Table III below shows the IC₅₀ values of representative compoundsaccording to general formula (I) (+=50 μM>IC₅₀>12.5 μM & ++=IC₅₀≦12.5μM).

Apoptosis Apoptosis Apoptosis Apoptosis Apoptosis Apoptosis Exampleinduction in induction in induction in induction in induction ininduction in No C8161 [μM] Hs578T [μM] SF126 [μM] SF763 [μM] U118 [μM]U138 [μM] 1 ++ ++ ++ + ++ ++ 7 ++ ++ − ++ + ++ 8 ++ ++ ++ ++ ++ + 10 ++++ + + ++ ++ 12 + 14 ++ ++ ++ ++ + ++ 15 ++ ++ ++ ++ − ++ 16 ++ ++ ++ ++− ++ 17 ++ ++ ++ ++ + ++ 18 ++ ++ ++ ++ ++ ++ 21 ++ ++ ++ ++ ++ + 24 ++25 ++ ++ ++ ++ ++ ++ 26 ++ ++ + ++ + ++ 27 ++ ++ + ++ ++ ++ 28 ++ ++ ++++ ++ ++ 29 ++ ++ ++ ++ − + 32 ++ ++ ++ ++ ++ ++ 33 ++ + ++ ++ + ++ 34++ + ++ ++ ++ ++ 35 ++ ++ ++ ++ ++ + 38 ++ ++ ++ ++ ++ ++ 41 ++ ++ ++ ++++ ++ 47 + ++ + ++ ++ ++ 55 ++ ++ ++ ++ + ++ 56 ++ ++ ++ ++ ++ ++ 57 ++++ ++ + ++ ++ 58 ++ + ++ ++ + ++ 59 ++ ++ ++ ++ ++ ++ 63 ++ ++ ++ ++ ++++ 70 ++ ++ ++ ++ ++ ++ 72 ++ ++ + ++ ++ + 75 ++ ++ ++ ++ ++ ++ 77 ++ ++++ ++ ++ ++ 80 + ++ + + ++ + 81 ++ ++ ++ ++ ++ ++ 82 ++ ++ ++ ++ ++ ++83 ++ ++ ++ ++ ++ ++ 84 ++ ++ ++ ++ ++ ++ 85 ++ ++ ++ ++ + ++ 86 ++ ++++ ++ ++ ++ 87 ++ ++ ++ ++ ++ + 88 ++ ++ ++ ++ ++ ++ 93 ++ ++ ++ ++ ++++ 95 ++ ++ ++ ++ ++ ++ 99 ++ ++ ++ ++ + ++ 100 ++ ++ ++ ++ + ++ 101 ++++ + ++ − ++ 102 ++ ++ ++ ++ ++ ++Assay Example D: Wound Healing Migration Assay

This method mimics cell migration during wound healing in vivo. Thebasic steps involve creating a “wound” in a cell monolayer, capturingthe images at the beginning and at regular intervals during cellmigration to close the wound, and comparing the images to quantify themigration rate of the cells. In detail, 150000 cell/24 well have beenseeded and allowed to form a monolayer overnight. Subsequently a “wound”or “scratch” has been performed with a 1000 μl pipette tip. The STDV ofwound size is normally below 10% at time point t0. The assay was stoppedby fixation with 0.05% Crystal violet/20% methanol when controlscratches were closed. The assay was terminated between 48 h and 72 hdepending on the migration potential of the indicated cell line. The“wounds” were visualized with a Zeiss Axiovert S100 microscope (CarlZeiss UK, Welwyn Garden City, UK). The tested compounds were used at12.5 μM, 6.25, 3.125 μM and DMSO control. IC50 values have beencalculated as 50% wound size in between t0 and t48 or t72.

Table IV below shows the IC₅₀ values of representative compoundsaccording to general formula (I) (4-=50 μM>IC₅₀>12.5 μM & ++=IC₅₀≦12.5μM).

Example IC50 Wound healing Assay/[μM] No SF763 C8161 A172 SF126 U118 1++ ++ ++ ++ ++ 4 ++ ++ ++ 6 ++ ++ ++ 7 ++ ++ ++ ++ ++ 8 ++ + ++ ++ ++ 10++ ++ ++ ++ ++ 11 + ++ + 12 ++ ++ ++ ++ 14 + + 15 ++ + 16 + + 17 + ++18 + ++ 21 + ++ 24 ++ 25 + + 26 ++ + 27 ++ + 28 ++ ++ 29 ++ ++ 32 ++ ++33 + ++ 34 + ++ 35 ++ ++ 38 + ++ ++ ++ ++ 40 ++ ++ ++ 41 ++ + 45 ++ ++++ 47 ++ ++ ++ ++ ++ 49 ++ ++ ++ 51 ++ ++ ++ 54 ++ ++ ++ 55 + + 56 + ++57 + ++ 58 ++ + 59 ++ + 63 ++ + 66 ++ ++ ++ 70 ++ + 72 ++ ++ 75 − + 77++ ++ ++ ++ ++ 78 ++ ++ ++ 80 ++ ++ 81 + ++ 82 ++ ++ 83 ++ ++ 84 + ++85 + ++ 86 + + 87 ++ + ++ ++ ++ 88 ++ + 93 + ++ 95 + + 99 ++ + ++ ++ ++100 ++ + ++ ++ ++ 101 + + 102 ++ + 104 + ++ ++ 110 ++ ++ ++ 112 ++ ++ ++119 ++ ++ ++ 151 ++ ++ ++ 155 ++ ++ ++ 156 ++ ++ ++ 157 ++ ++ ++ 158 ++++ ++ 177 ++ ++ ++ 178 ++ ++ ++ 179 ++ ++ + 181 ++ ++ ++ 184 ++ ++ ++209 ++ ++ ++ 210 ++ ++ ++Assay Example E: Matrigel Outgrowth Assay/Branching Assay

The Matrigel outgrowth assay is based on the ability of tumor cell topenetrate a solid gel of extracellular matrix proteins mimicking themetastasis formation in vivo. While cells with low invasive potentialappear as roundish cell or cell cluster, cells with high invasivepotential penetrate the Matrigel and form polymorphic structures. Indetail 65 μl of Matrigel matrix (Matrigel™ Matrix, BD Biosciences,Bedford, Mass., USA) with a concentration of 3 mg/ml have beenpolymerized in 96 well plates for 1 h at 37° C. Subsequently 5000cell/well were seeded into each well containing cell culture medium andindicated compound with concentrations of 3.125 μM, 1.56 μM and 0.78 μMas well as DMSO control. After 48 h, 72 h and 96 h images of cell weretaken on an inverted microscope using a 5× objective (Zeiss AxiovertS100 microscope Carl Zeiss UK, Welwyn Garden City, UK). Only compoundconcentrations were total branching inhibition was evident wereaccounted as positive. Method was used as previously described, withsome modifications (Thompson E W, et al. Association of increasedbasement membrane invasiveness with absence of estrogen receptor andexpression of vimentin in human breast cancer cell lines. J Cell Physio)1992; 150:534-44).

Table Va below shows the IC₅₀ values of representative compoundsaccording to general formula (I) (+=50 μM>IC₅₀>5.0 μM & ++=IC₅₀≦5.0 μM).

Total Total Total Total branching branching branching branchinginhibition in inhibition in inhibition in inhibition in Example MatrigelMatrigel Matrigel Matrigel No U118 [μM] U138 [μM] C8161 [μM] Hs578T [μM]1 ++ ++ ++ ++ 7 ++ + ++ + 8 ++ ++ ++ ++ 10 ++ + ++ ++ 12 ++ ++ ++ ++ 14++ + + + 15 ++ ++ ++ ++ 16 + ++ ++ + 17 ++ + ++ ++ 18 ++ ++ ++ ++21 + + + ++ 24 ++ + ++ ++ 25 ++ + ++ ++ 26 ++ + ++ ++ 27 ++ ++ ++ ++ 28++ ++ ++ + 29 ++ + ++ ++ 32 ++ + ++ ++ 33 ++ + ++ ++ 34 ++ + ++ ++ 35++ + ++ ++ 38 ++ + ++ ++ 41 ++ + ++ ++ 47 ++ + ++ ++ 55 ++ + ++ ++ 56++ + ++ + 57 ++ ++ + ++ 58 ++ + ++ ++ 59 + ++ ++ ++ 63 ++ ++ + ++ 66++ + ++ ++ 70 ++ ++ ++ ++ 72 ++ ++ ++ ++ 75 ++ + ++ ++ 77 ++ + + ++ 80++ + ++ ++ 81 + + ++ ++ 82 ++ + + ++ 83 ++ ++ ++ ++ 84 ++ ++ ++ ++ 85++ + ++ ++ 86 ++ + ++ ++ 87 ++ + ++ ++ 88 + + ++ + 93 ++ + ++ ++ 95 + +++ ++ 99 ++ ++ + ++ 100 ++ + ++ ++ 101 ++ + ++ + 102 ++ + ++ ++

Table Vb below shows the IC₁₀₀ values of representative compoundsaccording to general formula (I) (+=IC₁₀₀>12.5 μM & ++=IC₁₀₀ 12.5 μM).

Total branching inhibition in Matrigel/[μM] SK- NCI- Example No A172SF126 U118 PC3 U373 U138 MEL28 U87MG H1299 1 ++ ++ ++ ++ ++ ++ ++ + ++4 + ++ ++ 6 + ++ ++ 7 + ++ ++ 8 ++ ++ ++ 10 ++ ++ ++ 11 + + + 12 ++ ++++ ++ ++ ++ ++ + ++ 14 ++ ++ 24 ++ ++ ++ ++ ++ ++ ++ + ++ 38 ++ ++ +40 + ++ + 45 + ++ ++ 47 + ++ ++ 49 + + + 51 + ++ ++ 54 + ++ + 66 + ++ ++++ ++ ++ ++ ++ ++ 77 + ++ ++ 78 + ++ + 87 ++ ++ ++ 99 + ++ ++ 100 + ++++ 104 + + + 110 + ++ ++ 112 ++ ++ ++ 119 ++ ++ ++ 151 ++ ++ ++ 155 ++++ ++ 156 + ++ ++ 157 + ++ + 158 + ++ ++ 177 ++ ++ ++ 178 + ++ ++ 179 +++ ++ 181 + ++ ++ 184 + ++ ++ 209 ++ ++ ++ 210 + ++ ++Assay Example F: Boyden Chamber Migration Assay

The Boyden chamber assay is based on a chamber of two medium-filledcompartments separated by a microporous membrane of 8 μM (Cell cultureinsert 8.0 μM pore size, BD Biosciences, Bedford, Mass.). The boydenchamber migration assays were carried out according to the supplier'sinstructions. In general, 20000 cells are placed in the uppercompartment with medium containing 0% FCS plus 0.1% BSA and are allowedto migrate 16 h through the pores of the membrane into the lowercompartment, which is filled with cell culture medium containing 10% FCSas chemotactic agents. The cells remaining in the insert were removedwith a cotton swab, and the cells on the bottom of the filter were fixedand counted. (Zhang Y X, et al. AXL is a potential target fortherapeutic intervention in breast cancer progression. Cancer Res. 2008;68:1905-15).

Table VI below shows the IC₅₀ values of representative compoundsaccording to general formula (I) (+=50 μM>IC₅₀>5.0 μM & ++=IC₅₀≦5.0 μM).

IC50 Boyden Example chamber migration No assay Hs578T [μM] 1 ++ 7 ++ 8++ 10 ++ 14 ++ 15 ++ 16 ++ 17 ++ 18 ++ 21 ++ 25 ++ 26 ++ 27 ++ 28 ++ 29++ 32 ++ 33 ++ 34 ++ 35 ++ 24 ++ 38 + 41 ++ 47 ++ 55 ++ 56 ++ 57 + 58 ++59 ++ 63 ++ 70 ++ 72 ++ 75 ++ 77 ++ 80 ++ 81 ++ 82 + 83 ++ 84 ++ 85 ++25 ++ 86 ++ 87 ++ 88 ++ 93 + 95 ++ 99 ++ 100 ++ 101 ++ 102 ++ 86 ++ 87 +88 ++ 93 ++ 95 ++ 99 ++ 100 ++ 101 ++ 102 ++ 12 ++ 32 ++Assay Example G: Cell Viability Assay

Cell line ATCC no. Description HCT116 CCL-247 ™ Colorectal carcinoma;Aurora A wt amplification, Src expression HCT116 Colorectal carcinoma,p53 mutant def SW480 CCL-228 ™ Colorectal adenocarcinoma; Aurora Aamplification, p53 and ras mutation, is positive for expression ofc-myc, K-ras, H-ras, N-ras, myb, sis and fos oncogene HT29 HTB-28 ™Colorectal adenocarcinoma; is positive for expression of c-myc, K-ras,H-ras, N-ras, Myb, sis and fos oncogenes, p53 mutation, Aurora Aamplification H1993 CRL-5909 ™ adenocarcinoma, KEAP1 mutation, METamplification, CDK6 (copy number >=4 and <7) and CDK4 (copy number >=4and <7) amplification H1975 CRL-5908 ™ adenocarcinoma, EGFR mutant H1650CRL-5883 ™ adenocarcinoma, EGFR del mutant RKO CRL-2577 ™ Coloncarcinoma, wild type p53+ HCC827 CRL-2868 ™ adenocarcinoma, EGFR mutant,MYC and CDK4 (copy number >7) amplification H358 CRL-5807 ™bronchioalveolar carcinoma, RAS mutant H1666 CRL-5885 ™ adenocarcinoma;bronchoalveolar carcinoma RAF mutant A549 CCL-185 ™ lung carcinoma, EGFRand PLK mutant, wild type p53Conditions of Cell Viability Assay

Conditions reference compound: staurosporine conc 20 nM compound 10 μMcell number: 1000 cell/well volume: 100 μl/well incubation time: 72 hdetection: CellTiter-Glo Luminescent Cell Viability Assay

The CellTiter-Glo® Luminescent Cell Viability Assay (PromegaCorporation. Madison, Wis., USA) is method a determining the number ofviable cells in culture based on quantification of the ATP being presentwhich is an indicator of metabolically active cells was used accordingto manufacturers protocol. In detail the assay was performed in a 96well format were 1000 cells/well were incubated with compound atconcentration 10 μM as well as DMSO control for 72 h in 100 μl cellculture medium. Percentage of inhibition was calculated compared to ATPamount of DMSO control.

Table VII below shows the percentage (%) of viable cells in the culturetreated with representative compounds according to general formula (I)(a=0%-20% viable cells; b=21%-40% viable cells; c=41%-60% viable cells;d>60% viable cells).

HCT HCT Example 116wt 116def SW480 HT29 H1993 H1975 H1650 RKO HCC827H358 H1666 A549 1 a a a b b b c a b a c d 3 a a a a b b c a d a c b 7 ab a a b b a a a a b c 8 a a a b a a a b a a b c 10 a a a b a b b a a a bb 12 b b b b c c b a b a c d 13 a a a a a a b a a a a b 14 a b a a a b ba b b c c 15 d d b c b c c c d c c d 16 c c a b b a b b c a c c 18 a a aa a a b a b a b b 19 a b a a a b b a b a b b 20 a b a a b b b a c a b d21 d c b b b c c c d b c d 22 b b a a a a b b b a b d 23 a a a a a a b ab a b c 27 a a a b a b c a d a c d 28 b b a b b b b a b a c b 29 a a a aa a b a b b c c 32 a b b a a b b b c a c c 33 a b a a a b d a b b b c 34a b a b a a b a d a b d 35 a b a a b a b c c a b d 38 b b a a b b d a ca b d 41 c a a b b a c a c a b b 47 a b b c a a c a c a b c 55 a b b b ad a c c a a b 56 b b a a c a c b b a b d 57 d b a a b a c a d b c d 58 ab a a c a d a d b b c 59 a a a a a b d a b b c b 63 a b a b a a c d b ac b 70 c b b b a a c a b b b b 72 b c a a a c c a c b b d 75 b b a a b ab a d a c d 77 a b a c b a b b d a c c 80 b b a c a a d a b a b d 81 b ba b b a b c a a b c 82 a b b a a b b c b b c d 83 a b b a a c b d a a bb 84 a a a a a b a a d a c d 85 a b a b a b b a a b c c 86 b b b a a b bb c a c d 87 c a a a c a b c c a c d 88 c a b b a a c c a a b c 93 d b aa b a b a b a b d 95 b b a a a a b a b a b d 99 a d a b b b b b c a c b100 a a a b c c b a b a b d 101 b b a a b c c a b a c c 102 a a a a b bc b b a c cAssay Example H: Cancer Cell Line Based Cellular Kinase Assay

Indicated cancer cell lines were seeded onto 6-well plates (1.5×10⁵cells/well) in 1.5 ml DMEM+10% heat inactivated FBS (GIBCO-InvitrogenGmbH, Karlsruhe, Germany) and cultured overnight, followed by serumdepletion in DMEM without FBS for 24 h. Serial dilutions of compoundswere added, and the cells were incubated for 1 h followed by Gas6mediated Axl activation with 250 ng/ml recombinant human Gas6 (CatalogNumber: 885GS, R&D Systems, Inc., Minneapolis, USA) for 30 minutes.Cells were washed with PBS and lysed on ice in 500 μl lysis buffer (50mM HEPES (pH 7.5), 150 mM NaCl, 1 mM EGTA, 10% Glycerol, 1% TritonX-100, 100 mM NaF, 10 mM Na₄P₂O₇.10 H₂O, 1 mM Na₃VO₄, 1 mMphenylmethylsulfonyl fluoride, and 10 mg/ml aprotinin) for 15 min. Thecell lysate were used for phosphotyrosine AXL enzyme-linkedimmunosorbant assay (pY-AXL-ELISA). 96-well Nunc MicroWell™ plates(Fischer Scientific GmbH, Schwerte, Germany) were coated over night withhomemade anti-Axl capture antibody 2 μg/ml (clone 259/2, IgG1 isotype)in PBS (100 μl/well). Subsequently 96-well plates were blocked withPBS-0.05% Tween®20+10% FBS for 4 h at 37° C. Plates were washed 5 timeswith PBS-0.05% Tween®20 and 95 μl of lysate was transferred per well forincubation overnight at 4° C. Plates were washed 5 times with PBS-0.05%Tween®20 (Sigma, Steinheim, Germany). For detection of phosphorylatedtyrosine we used homemade biotynilated 4G10-antibody (0.5 μg/ml) inPBS-0.05% Tween®20+10% FBS (100 μl/well) and incubated the 96-well platefor 2 h at room temperature. The anti-phosphotyrosine mouse monoclonalantibody 4G10 was biotynilated with Sulfo-NHS®-Biotin according to thesuppliers protocol (Pierce, Rockford, Ill., USA) and purified by MircoBio-Spin 6 Chromatograpy Columns (BIO RAD Laboratories, Inc., Hercules,Calif., USA) using PBS as diluent. Plates were washed 5 times withPBS-0.05% Tween®20. For biding to biotin Alkaline Phosphatase ConjugatedStrepavidin SA110 (Millipore, Billerica, Mass., USA) (1:4000) was usedin PBS-0.05% Tween®20+10% FBS (100 μl/well) and incubated for 30 min atroom temperature. Plates were washed 5 times with PBS-0.05% Tween®20.For fluorimetric detection of alkaline phosphatase AttoPhos SubstrateSet (Roche diagnostics GmbH, Mannheim, Germany) was used (100 μl/well).The fluorimetric signal was quantified after 90 min at 430/560 nmwavelength using a TECAN Ultra Evolution plate reader (Tecan DeutschlandGmbH, Crailsheim, Germany).

Table VIII below shows the IC₅₀ values of representative compoundsaccording to general formula (I) (+=50 μM>12.5 μM & ++=IC₅₀≦12.5 μM).

Cell Origin line AXL TC AXL TC AXL TC AXL TC Breast Hs578T 24 ++ 12 1 66Breast MDA- ++ 24 ++ 12 ++ 1 ++ 66 MB231 Brain SF126 ++ 24 ++ 12 ++ 1 ++66 Brain U118 + 24 ++ 12 ++ 1 ++ 66 Brain U138 ++ 24 ++ 12 ++ 1 ++ 66Brain U373 ++ 24 ++ 12 ++ 1 ++ 66 Brain U87MG − 24 + 12 + 1 − 66 BrainA172 ++ 24 ++ 12 ++ 1 ++ 66 Skin C8161 + 24 + 12 + 1 + 66 Skin SK- −24 + 12 + 1 − 66 MEL-28 Pancreas ASPC-1 ++ 24 ++ 12 ++ 1 ++ 66 ProstatePC3 + 24 ++ 12 ++ 1 ++ 66 Prostate DU145 ++ 24 ++ 12 ++ 1 ++ 66 LungH460 ++ 24 ++ 12 ++ 1 ++ 66 Lung A549 ++ 24 ++ 12 ++ 1 ++ 66 Lung H1299++ 24 ++ 12 ++ 1 ++ 66 TC: tested compound (3 μM-0.1 μM) AXL: Inhibitionof AXL-pY

The invention claimed is:
 1. Compounds having the general formula (I):

wherein —R¹ or —R² represents —O—X—R⁸; if —R¹ represents —O—X—R⁸ then—R² represents —H, —OH, —OCH₃, —OCF₃, —OC₂H₅, —OC₃H₇, —OCH₂CH₂—OCH₃,—OCH₂CH₂—OC₂—H₅; if —R² represents —O—X—R⁸ then —R¹ represents —H, —OH,—OCH₃, —OCF₃, —OC₂H₅, —OC₃H₇, —OCH₂CH₂—OCH₃, —OCH₂CH₂OC₂H₅; —X—represents —CR¹¹R¹²—CR¹³R¹⁴—, —CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—,—CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—,—CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—,—CR¹¹R¹²—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²¹R²²—, —(CH₂)_(n)NH—, —CO—,—(CH₂)_(n)—CO—, —(CH₂)_(n)—NH—CO—NH—, —(CH₂)_(n)—NH—CO—,—(CH₂)_(n)—NH—CO—O—, —(CH₂)_(n)—CO—NH—, —(CH₂)_(n)—O—CO—NH—,—(CH₂)_(n)—O—CO—, —(CH₂)_(n)—O—, —(CH₂)_(n)—; n is an integer selectedfrom 1, 2, 3, 4, 5 and 6; —R³, —R⁴, —R⁵, —R⁶ are independently of eachother selected from hydrogen, halogen, nitro, C₁₋₆ alkyl,C₃-C₁₀-cycloalkyl, C₁₋₆ alkoxy, wherein the C₁₋₆ alkyl,C₃-C₁₀-cycloalkyl or C₁₋₆ alkoxy groups are optionally mono- orpolysubstituted by hydroxyl, halogen, C₁₋₄ alkyl and/or C₁₋₄ alkoxy,wherein the C₁₋₄ alkyl and/or C₁₋₄ alkoxy groups are optionally mono- orpolysubstituted by hydroxyl and/or halogen; —R⁷ represents (i) asaturated or unsaturated three- to twelve-membered carbocyclic orheterocyclic ring system which is optionally mono- or polysubstituted byhydroxy, C₁₋₆ alkyl, C₃-C₁₀-cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, a halogen atom, or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group, and the C₁₋₆ alkyl,C₃-C₁₀-cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy groupsare optionally substituted by a halogen atom or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group,(ii) C₁₋₆ alkyl or C₁₋₆ alkoxy which is unsubstituted or substituted bya saturated or unsaturated three- to twelve-membered carbocyclic orheterocyclic ring system which is optionally mono- or polysubstituted byhydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, a halogenatom, or a saturated or unsaturated three- to eight-membered carbocyclicor heterocyclic group, and the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ alkoxy groups are optionally substituted by a halogen atom or asaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group, (iii) a nitrogen atom substituted with a saturatedor unsaturated three- to twelve-membered or heterocyclic ring systemwhich is optionally mono- or polysubstituted by hydroxy, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, a halogen atom, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup, and the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxygroups are optionally substituted by a halogen atom or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group,—R⁸ represents

R¹¹—R²² represent independently of each other linear or branched,substituted or unsubstituted C₁-C₂₀-alkyl, —H, —OH, —OCH₃, —OC₂H₅,—OC₃H₇, —O-cyclo-C₃H₅, —OCH(CH₃)₂, —OC(CH₃)₃, —OC₄H₉, —OPh, —OCH₂-Ph,—OCPh₃, —SH, —SCH₃, —SC₂H₅, —SC₃H₇, —S-cyclo-C₃H₅, —SCH(CH₃)₂,—SC(CH₃)₃, —NO₂, —F, —Cl, —Br, —I, —N₃, —CN, —OCN, —NCO, —SCN, —NCS,—CHO, —COCH₃, —COC₂H₅, —COC₃H₇, —CO-cyclo-C₃H₅, —COCH(CH₃)₂, —COC(CH₃)₃,—COOH, —COCN, —COOCH₃, —COOC₂H₅, —COOC₃H₇, —COO-cyclo-C₃H₅,—COOCH(CH₃)₂, —COOC(CH₃)₃, —OOC—CH₃, —OOC—C₂H₅, —OOC—C₃H₇,—OOC-cyclo-C₃H₅, —OOC—CH(CH₃)₂, —OOC—C(CH₃)₃, —CONH₂, —CONHCH₃,—CONHC₂H₅, —CONHC₃H₇, —CONH-cyclo-C₃H₅, —CONH[CH(CH₃)₂], —CONH[C(CH₃)₃],—CON(CH₃)₂, —CON(C₂H₅)₂, —CON(C₃H₇)₂, —CON(cyclo-C₃H₅)₂,—CON[CH(CH₃)₂]₂, —CON[C(CH₃)₃]₂, —NH₂, —NHCH₃, —NHC₂H₅, —NHC₃H₇,—NH-cyclo-C₃H₅, —NHCH(CH₃)₂, —NHC(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(C₃H₇)₂,—N(cyclo-C₃H₅)₂, —N[CH(CH₃)₂]₂, —N[C(CH₃)₃]₂, —SOCH₃, —SOC₂H₅, —SOC₃H₇,—SO-cyclo-C₃H₅, —SOCH(CH₃)₂, —SOC(CH₃)₃, —SO₂CH₃, —SO₂C₂H₅, —SO₂C₃H₇,—SO₂-cyclo-C₃H₅, —SO₂CH(CH₃)₂, —SO₂C(CH₃)₃, —SO₃H, —SO₃CH₃, —SO₃C₂H₅,—SO₃C₃H₇, —SO₃-cyclo-C₃H₅, —SO₃CH(CH₃)₂, —SO₃C(CH₃)₃, —OCHF₂, —OCF₃,—OC₂F₅, —O—COOCH₃, —O—COOC₂H₅, —O—COOC₃H₇, —O—COO-cyclo-C₃H₅,—O—COOCH(CH₃)₂, —O—COOC(CH₃)₃, —NH—CO—NH₂, —NH—CO—NHCH₃, —NH—CO—NHC₂H₅,—NH—CO—NHC₃H₇, —NH—CO—NH-cyclo-C₃H₅, —NH—CO—NH[CH(CH₃)₂],—NH—CO—NH[C(CH₃)₃], —NH—CO—N(CH₃)₂, —NH—CO—N(C₂H₅)₂, —NH—CO—N(C₃H₇)₂,—NH—CO—N(cyclo-C₃H₅)₂, —NH—CO—N[CH(CH₃)₂]₂, —NH—CO—N[C(CH₃)₃]₂,—NH—CS—NH₂, —NH—CS—NH-cyclo-C₃H₅, —NH—CS—NHC₃H₇, —NH—CS—NH[CH(CH₃)₂],—NH—CS—NH[C(CH₃)₃], —NH—CS—N(CH₃)₂, —NH—CS—N(C₂H₅)₂, —NH—CS—N(C₃H₇)₂,—NH—CS—N(cyclo-C₃H₅)₂, —NH—CS—N[CH(CH₃)₂]₂, —NH—CS—N[C(CH₃)₃]₂,—NH—C(═NH)—NH₂, —NH—C(═NH)—NHCH₃, —NH—C(═NH)—NHC₂H₅, —NH—CS—NHC₂H₅,—NH—C(═NH)—NHC₃H₇, —NH—C(═NH)—NH-cyclo-C₃H₅, —NH—C(═NH)—NH[CH(CH₃)₂],—NH—C(═NH)—NH[C(CH₃)₃], —NH—CS—NHCH₃, —NH—C(═NH)—N(CH₃)₂,—NH—C(═NH)—N(C₂H₅)₂, —NH—C(═NH)—N(C₃H₇)₂, —NH—C(═NH)—N(cyclo-C₃H₅)₂,—Si(CH₃)₃, —NH—C(═NH)—N[CH(CH₃)₂]₂, —NH—C(═NH)—N[C(CH₃)₃]₂, —O—CO—NH₂,—O—CO—NHCH₃, —O—CO—NHC₂H₅, —O—CO—NHC₃H₇, —O—CO—NH-cyclo-C₃H₅,—O—CO—NH[CH(CH₃)₂], —O—CO—NH[C(CH₃)₃], —O—CO—N(CH₃)₂, —O—CO—N(C₂H₅)₂,—O—CO—N(C₃H₇)₂, —O—CO—N(cyclo-C₃H₅)₂, —O—CO—N[CH(CH₃)₂]₂,—O—CO—N[C(CH₃)₃]₂, —O—OC—OCH₃, —O—CO—OC₂H₅, —O—CO—OC₃H₇,—O—CO—O-cyclo-C₃H₅, —O—CO—OCH(CH₃)₂, —O—CO—OC(CH₃)₃, —CH₂F —CHF₂, —CF₃,—CH₂Cl, —CHCl₂, —CCl₃, —CH₂Br —CHBr₂, —CBr₃, —CH₂I —CHI₂, —CI₃, —CPh₃,—CH₂—CH₂F—CH₂—CHF₂, —CH₂—CF₃, —CH₂—CH₂Cl, —CH₂—CHCl₂, —CH₂—CCl₃,—CH₂—CH₂Br —CH₂—CHBr₂, —CH₂—CBr₃, —CH₂—CH₂I —CH₂—CHI₂, —CH₂—Cl₃, —CH₃,—C₂H₅, —C₃H₇, -cyclo-C₃H₅, —CH(CH₃)₂, —C(CH₃)₃, —C₄H₉, —CH₂—CH(CH₃)₂,—CH(CH₃)—C₂H₅, —C(CH₃)₃, -Ph, —CH₂-Ph, —CH═CH₂, —CH₂—CH═CH₂,—C(CH₃)═CH₂, —CH═CH—CH₃, —C₂H₄—CH═CH₂, —CH═C(CH₃)₂, —C≡CH, —C≡C—CH₃,—CH₂—C≡CH; and stereoisomeric forms, solvates, hydrates and/orpharmaceutically acceptable salts thereof.
 2. Compound according toclaim 1, wherein the group R⁸—X—O— is:

wherein the substituent —R²² refers to phenyl, benzyl, C₁-C₆-alkyl,pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, —OH, —CH₂—OH, —C₂H₄—OH,—OCH₃, —CH₂—OCH₃, —C₂H₄—OCH₃; C₁-C₆-alkyl refers to —CH₃, —C₂H₅, —C₃H₇,—CH(CH₃)₂, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —CH(CH₃)—C₃H₇,—CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C₅H₁₁, —C(CH₃)₂—C₂H₅,—CH₂—C(CH₃)₃, —CH(C₂H₅)₂, —C₂H₄—CH(CH₃)₂, —C₆H₁₃, —C₃H₆—CH(CH₃)₂,—C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,—CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,—CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃, and—CH(CH₃)—C(CH₃)₃, wherein in the afore-mentioned groups one or morehydrogen atom(s) can be replaced by —OH, —OCH₃, —OC₂H₅, —SH, —SCH₃,—SC₂H₅, —NO₂, —F, —Cl, —Br, —I, —N₃, —COCH₃, —COC₂H₅, —COOCH₃, —COOC₂H₅,—OOC—CH₃, —OOC—C₂H₅, —COOH, —CONH₂, —CON(CH₃)₂, —CON(C₂H₅)₂, —NH₂,—NHCH₃, —NHC₂H₅, —N(CH₃)₂, —N(C₂H₅)₂, —SOCH₃, —SOC₂H₅, —SO₃H, —OCF₃,—CF₃, —C≡CH.
 3. Compound according to claim 1, wherein the compound isselected from the group comprising:2,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,Biphenyl-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-phenoxy-benzenesulfonamide,2-Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,2,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,4-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-methoxy-benzenesulfonamide,2-Bromo-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-nitro-benzenesulfonamide,3-Fluoro-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,3-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide,2-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,4-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methyl-benzenesulfonamide,2-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,3-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide, Thiophene-2-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,2,6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,N-(3-Fluoro-4-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,N-(3-Fluoro-4-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide,N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl-phenyl)-2-trifluoromethyl-benzenesulfonamide,2,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,N-{4-[6,7-Bis-(2-methoxy-ethoxy)-quinolin-4-yloxy]-3-fluoro-phenyl}-2,6-difluoro-benzenesulfonamide,{4-[2-Fluoro-4-(2-fluoro-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-aceticacid ethyl ester,2-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-N,N-dimethyl-acetamide,Cyclohexanecarboxylic acid4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-ylester,N-(3-Fluoro-4-{6-methoxy-7-[3-(tetrahydro-pyran-4-ylamino)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,N-{4-[7-(3-Cyclopropylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,N-{4-[7-(3-Cyclobutylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,N-(4-{7-[3-(3-tert-Butyl-ureido)-propoxy]-6-methoxy-quinolin-4-yloxy}-3-fluoro-phenyl)-2-trifluoromethyl-benzenesulfonamide,N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,N-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-trifluoromethyl-benzenesulfonamide,N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide2,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamideN-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-fluoro-benzenesulfonamideN-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,5-difluoro-benzenesulfonamideBenzo[b]thiophene-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amideBenzo[b]thiophene-3-sulfonic acid(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amideN-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide2,6-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide2,5-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide2,5-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide2,6-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamideN-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide2,5-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide2,6-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamideThiophene-2-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide5-Chloro-thiophene-2-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide5-Methyl-thiophene-2-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amideN-[5-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-4-methyl-thiazol-2-yl]-acetamideThiophene-3-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide2,5-Dichloro-thiophene-3-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide3-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylicacid methyl ester Benzo[b]thiophene-3-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amideFuran-2-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide3,5-Dimethyl-isoxazole-4-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide1-Methyl-1H-pyrazole-3-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide1-Ethyl-1H-pyrazole-4-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide2-Methyl-1H-imidazole-4-sulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amideCyclopropanesulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide2-Phenyl-ethenesulfonic acid(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenylsulfamoyl)-thiophene-2-carboxylicacid methyl ester 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide1-Methyl-1H-pyrazole-3-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide2-Methyl-3H-imidazole-4-sulfonic acid(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide.4. Compound according to claim 1 for use as a pharmaceutically activeagent in medicine.
 5. Pharmaceutical composition comprising at least onecompound according to claim 1 as an active ingredient, together with atleast one pharmaceutically acceptable carrier, excipient and/ordiluents.